DEVELOPMENTAL THERAPEUTICS—MOLECULARLY TARGETED AGENTS AND TUMOR BIOLOGY

Taking Aim at the Undruggable

Niamh Coleman, MD, PhD, and Jordi Rodon, MD, PhD

The term “undruggable” is used to describe a protein that is not pharmacologically capable of being targeted;
overview

recently, however, substantial efforts have been made to turn these proteins into “druggable” targets. Thus,
“difficult to drug” or “yet to be drugged” are perhaps more appropriate terms. In cancer, a number of elusive
targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmaco-
logically targeting these intractable proteins is now a key challenge of modern drug development, requiring
innovation and the development of new technologies. In this article, we discuss some of the recent technologic
and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe
recent successes in drugging the undruggable RAS (KRAS G12C and HRAS), and discuss the advances that
have led to the validation of further targets previously believed to be undruggable, such as HIF-2α, BCL-2,
MDM2, and MLL. Finally, we look to the future and describe important advances that are likely to have a major
impact on targeting undruggable targets, such as the advent of proteolysis-targeting chimeras and protein-
protein modulators, which are leading to considerable excitement surrounding the development of cancer
targets.

CONCEPTS development risks, and patient convenience, that

If we look at the relationship among the human pro-
teome, diseases, and drugs (approved or in develop-
ment), it is striking to realize that only between 1% and
2% of disease-modifying proteins are known, or pre-
dicted, to be druggable. In therapeutics, the most
frequent drug target is catalytic sites of proteins, but
there are other entities that could be modulated for
therapeutic intent, such as nucleic acids (and nucleic
acid complexes [e.g., ribosomes]), intracellular small
molecules, and protein-protein or protein–nucleic acid
interactions. Druggability,1 then, can be defined as the
property of a target for being known, or predicted, to
bind with high affinity to a drug and modulate its
function with a therapeutic benefit. There are several
methods to predict target druggability, based on em-
pirical analyses of libraries of compounds or based on
structural analysis. “Drug likeness” refers to the
compounds that bind the target. The concept includes
the properties that enable pharmaceutical attributes of
Author affiliations a viable therapeutic entity, such as structural, physi-
and support cochemical (e.g., chemical stability, solubility), phar-
information (if
macokinetic (e.g., bioavailability, distribution), and
applicable) appear
at the end of this
toxicity characteristics. Related to druggability (of the
article. target) and drug likeness (drug candidate) is the
Accepted on March concept of “developability,” which considers the whole
24, 2021, and process, from target discovery and lead compound
published at development to its clinical entry. In addition to the
ascopubs.org on May
14, 2021: DOI https://
preclinical pharmacokinetic/pharmacodynamic prop-
doi.org/10.1200/ erties, it encompasses factors, such as physiochemical
EDBK_325885 properties, formulation, performance, manufacturability,
enable the development of a drug candidate.
In cancer, some of these disease-modifying targets
seem difficult to address; they seem “undruggable”
because they lack accessible deep hydrophobic
pockets where ligands and drugs can bind, or they lack
enzymatic activity (have no active site), referring to the
loss of function of the target. In cancer, the classic
undruggables include β-catenin, RAS, and transcrip-
tion factors (e.g., STAT3, TP53, MYC).2 Some recent
technologic advances have eroded the concept of
undruggability, including structural biology advances
(protein nuclear magnetic resonance and crystal
structures), three-dimensional annotated chemical li-
braries, and novel computational methods to visualize
or predict aspects of molecular targets and in-
teractions. Other advances in pharmacology have
contributed as well, including expanded reengineered
therapeutic antibodies and biologics, strategies to
enable the selective degradation of specific proteins,
and improved delivery systems for nucleic acid–based
compounds.2 In this article, we review the later de-
velopments, addressing how some new molecular
entities show encouraging signs that they will change
the landscape of undruggability.
HISTORICAL PERSPECTIVE
In the early 20th century, drug discovery was initially
based on random screening for active substances from
biologic extracts (e.g., plants, microorganisms). For
cancer drug development, the attention initially was
focused on cytotoxic agents aiming at DNA replication,

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 Coleman and Rodon
PRACTICAL APPLICATIONS
• Recent successes in targeting KRAS G12C and
HRAS represent significant advances in drug-
ging “the undruggable” and provide proof of
concept.
• Pharmacologic targeting of intractable proteins
is now a key challenge of modern drug devel-
opment, requiring innovation and the devel-
opment of new technologies.
• Important advances that are likely to have
a major impact on targeting undruggable tar-
gets include the advent of proteolysistargeting
chimeras and protein-protein modulators,
which are leading to considerable excitement in
the field of drug development.
mitotic machinery, or DNA integrity, targeting, for example,
dihydrofolate reductase and topoisomerase. The advent of
molecular biology fueled efforts to seek drugs directed
against relevant molecular targets, such as growth factor
receptors, enzymes, or other biologic targets driving the
disease. Alongside the development of targeted therapies,
in the 1970s the pharmacologic industry moved toward
a rational drug discovery methodology of small molecules.
Marked advancements in the experimental and computa-
tional techniques used in the drug discovery process have
changed the development of small molecules and anti-
bodies, moving from an empirical screening toward
a structured rational design. With the parallel development
of recombinant protein-based therapeutic agents in the
1980s, rational development became the standard practice.
Thus, the modern drug development paradigm was born.3
When considering the class of drugs approved by the U.S.
Food and Drug Administration for management of cancer
under this paradigm, the vast majority fall into two cate-
gories: small-molecule drugs (those with composite mo-
lecular mass , 1,000 daltons) and protein therapeutics or
biologics (primarily monoclonal antibodies, some peptides,
and a few vaccines). Until now, biologics have been
designed to bind to specific target epitopes in extracellular
or cell surface targets, whereas small chemical entities are
intended to access and modulate intracellular proteins.
Typically, small molecules bind to accessible hydrophobic
invaginations in the target, more frequently in the catalytic
site (also known as catalytic inhibitors; e.g., erlotinib,
sunitinib, or copanlisib), as well as in other sites, “an al-
losteric site,” but altering the shape of the active site so that
the target can no longer bind to its substrate (“allosteric
inhibitors” such as everolimus or trametinib). Although it
depends on their size and chemical properties, most small
molecules developed as anticancer agents are orally
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available. Biologics, in contrast, can interact with larger
surfaces; however, because of their larger molecular size,
they have limited delivery, requiring intravenous treatment
and targeting only extracellular targets (e.g., EGFR, HER2,
VEGFR2, PD-1). In cancer, many validated drug targets are
druggable with small molecules or antibodies: serine/threonine/
tyrosine kinases, growth factor receptors, and receptor ligands.
Other classes of cancer molecular targets seem difficult to
address by either of these two classes of agents: the so-called
undruggable targets.
New Technologies and Pharmacologic Entities Enable
Drugging the Undruggable
Along with tumor heterogeneity and drug-resistance
mechanisms, developing therapeutics for apparently in-
tractable targets is one of the key challenges of targeted
therapeutics. Novel chemical entities are now being de-
veloped that may change the tide. Some examples of
chemical entities, beyond the classic inhibitors of kinases,
include protein-protein interaction (PPI) modulators, mul-
tifunctional small molecules (e.g., proteolysis-targeting
chimeras [PROTACs]), peptides/peptidomimetics, nucleic
acid–based therapeutics (e.g., oligonucleotides), and even
cell therapies and T-cell receptor (TCR) mimetics. This
major expansion of the “chemical matter” (chemical space
used in drug discovery) used for therapeutics brings along
new chemical, biologic, and pharmaceutical properties that
could enable the modulation of difficult targets. Because of
some of the characteristics of these compounds, most of
these entities may require intravenous delivery; however,
nanomedicine approaches could reduce dosing frequency,
while improving therapeutic windows.
Of these novel compound types, one notable recent success
is venetoclax, a first-in-class BCL-2 inhibitor. It took 20 years
of extensive chemistry efforts,4,5 several lead candidates,
and many clinical trials, but its approval by the U.S. Food
and Drug Administration in 2016 demonstrated the possi-
bility of developing agents that impede PPIs with small
molecules. Since that time, BCL-2 is no longer on the list of
undruggables.
The recent successes with targeting KRAS G12C and HRAS
are also important breakthroughs in targeting the undrug-
gable. The three RAS oncogene products, KRAS, NRAS,
and HRAS, have been among the most interesting, sought
after, and challenging targets, in part because of the fre-
quency of these lesions (approximately 30% of human
cancers). In the case of KRAS G12C, the breakthrough
came from structural insights provided by x-ray crystallog-
raphy and nuclear magnetic resonance that showed that
this specific mutation creates a pocket that can be exploited
therapeutically. Using state-of-the-art chemistry, pharma-
cologists have been able to synthesize covalent inhibitors
that attach to Cys12, thereby inhibiting MAPK signaling.
 Taking Aim at the Undruggable
Sotorasib is one such small-molecule inhibitor, and its use
has resulted in confirmed objective response rates (com-
plete or partial response) of 32.2% in patients with KRAS
G12C non–small cell lung cancer, as well as disease control
rates (objective response or stable disease) of 88.1% in
non–small cell lung cancer and 73.8% in colorectal can-
cer.6 Consequently, several additional compounds are in
clinical development.
In the case of HRAS, the breakthrough came from the
observation of the exquisite dependency of HRAS on far-
nesyl transferase for prenylation, a critical step that is
necessary for RAS to bind to the inner layer of the cell
membrane and function (other members of the RAS family
have redundant pathways). Tipifarnib, a farnesyl transferase
inhibitor, has been granted fast track designation by the
U.S. Food and Drug Administration for the treatment of
patients with HRAS-mutant head and neck squamous cell
carcinomas. Early clinical trials are showing an overall re-
sponse rate of 50.0% (95% CI, 26.0–74.0) and a median
duration of response of 14.7 months (95% CI, 2.1–not
reported) in patients with these diseases.7
Another recent success story related to the use of modern
crystallography and structure-based design is the targeting
of HIF-2α. von Hippel-Lindau disease and many clear cell
renal cell carcinomas have inactivating mutations in VHL,
resulting in constitutive activation of the HIF-2α transcrip-
tion factor. The finding of a large cavity within the HIF-2α
PAS-B domain permitted the development of molecules
(e.g., PT2399, PT2385, and PT2977, later known as MK-
6482) that bind to the allosteric site and block its di-
merization with the HIF-1α/2α transcriptional dimerization
partner ARNT/HIF-1β. Treatment of 61 patients with VHL-
associated clear cell renal cell carcinoma using MK-6482
(NCT03401788) showed a confirmed response rate of
27.9%, as well as 13.1% unconfirmed responses at the time
of reporting (86.9% of patients experienced some decrease
in the size of their target lesions).8 This was the first story of
successful drug development against a transcription factor.
Some other programs are aiming to develop multispecific
drugs. These compounds work through two or more
chemical entities (one effector and one target), with several
drug-target binding interfaces that work sequentially or
concurrently. This multispecificity allows limiting drug ac-
tivity to a specific location or anchors the target close to an
endogenous effector, allowing the effector to modulate the
target. Some of them are antibody/peptide-based, such as
heteroduplex immunoglobulin G, bispecific CD3 engagers,
or antibody-toxin, antibody-drug, or antibody-cytokine fu-
sion proteins. Others are small molecules called “match-
makers,” which pull two entities together (the effector and
target), such that one (the effector) acts upon the other (the
target). These act as chemical inducers of degradation
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utilizing endogenous biologic mechanisms, such as the
ubiquitin-proteasome degradation system: the therapeutic
effect is produced by modulating protein levels of the target.
PROTEOLYSIS-TARGETING CHIMERAS
PROTACs are one class of bifunctional small molecules.
They simultaneously bind to a target protein and an
E3 ubiquitin ligase, thereby causing ubiquitylation and
degradation of the target protein (Fig. 1).9 The ability of
PROTACs to degrade proteins, regardless of their function,
makes this approach highly attractive, especially for those
targets for which compounds can be developed that bind to
a given target without inhibiting its activity. Degradation of
the target protein by PROTACs is also suitable for targets
that overcome the effect of an inhibitor by overexpression,
which is often seen in cancer. As such, targeted protein
degradation offers tremendous promise. In fact, PROTACs
have a number of advantages; because of their unique
mechanism of action, a PROTAC molecule is capable of
catalyzing the degradation of multiple molecules of the
protein of interest. Consequently, compared with small-
molecule inhibitors, PROTACs may require significantly
lower concentrations to elicit a desired pharmacologic ef-
fect. PROTACs also have the potential to target so-called
undruggable proteins, such as transcription factors. For
example, STAT3 is a key factor for cell survival, proliferation,
angiogenesis, metastasis, and chemotherapy resistance;
thus, blocking STAT3 activity is an attractive strategy that
has been pursued for many years, with little success.10
However, PROTACs targeting STAT have been recently
reported,11,12 opening new possibilities.
PROTACs can be used to overcome drug resistance re-
sulting from mutations of a protein of interest, such as
PROTACs targeting mutated forms of BCR-ABL,13 receptor
tyrosine kinases,14 estrogen receptor-α,15 and Bruton ty-
rosine kinase.16 PROTACs can overcome resistance to
small-molecule inhibitors resulting from target upregulation
by degrading the target; one such example is androgen
receptor degraders, which have recently overcome re-
sistance developed to the androgen receptor antagonist
enzalutamide during prostate cancer treatment.17
Although the field of PROTAC research is still relatively
new, these rapid exciting clinical developments, such as
PROTAC-mediated targeting of androgen receptors, dem-
onstrate proof of principle, proving that this approach is
broadly applicable. Numerous proteins are now reported to
have been degraded in this manner, including Bruton ty-
rosine kinase, BCR-Abl, FKBP12, BRD9, and CDK6.18
One of the most exciting and compelling aspects of
unlocking the vast potential of protein degraders is the
opportunity to bring the wide variety of the historically
undruggable proteome into play for therapeutic benefit. In
spite of these promising prospects, there are challenges in
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 Coleman and Rodon

FIGURE 1. General Mechanism of Proteolysis-Targeting Chimera–Induced Degradation of the Protein of Interest

A proteolysis-targeting chimera molecule recruits an E3 ligase to a protein of interest, followed by polyubiquitin of the latter by an E2-conjugating enzyme.
The polyubiquitinated protein of interest is recognized by the proteasome for its degradation. The proteolysis-targeting chimera molecule is recycled to
induce the next round of degradation.

utilizing PROTAC molecules, such as attaining suitable
physicochemical properties; adequate absorption, distri-
bution, metabolism, and excretion properties for oral dosing;
and/or even achieving adequate central nervous system
exposure.18 Therefore, overcoming some of these phar-
macologic obstacles will undoubtedly be essential in paving
the way for the broader therapeutic potential of PROTAC
molecules.
Small Molecules Modulating Protein-Protein Interactions
also typically large, larger than that of the receptor-ligand
contact area,26,27 and is highly hydrophobic.24,26 In addition,
the amino acid residues involved in PPIs result in high-
affinity binding between the proteins, making it more
challenging for small molecular compounds to inhibit.28
Compared with traditional drug target enzymes or re-
ceptors, PPIs also lack endogenous ligands,28 and com-
pared with traditional small-molecule drugs, drugs acting on
PPIs have a higher molecular weight (. 400 daltons).

Critical biologic processes, such as DNA replication, tran-
scription, translation, and transmembrane signal trans-
duction, rely on functional specific proteins that are
regulated through protein complexes and controlled via
PPIs19,20; aberrant PPIs are associated with many human
cancers.21 In contrast with small molecules targeting
protein-ligand interactions (found in enzymes, ion channels,
or receptors), targeting PPIs, previously regarded as
undruggable targets, is a more challenging and novel
therapeutic approach.22
Designing a small molecule to bind to a PPI interface has
proven to be difficult for a number of reasons. First, the
unique interface structure is a challenge for drug design:
compared with the binding pockets of conventional protein
targets, the interface of PPIs tends to be flat and contains
few pockets, making it difficult for small-molecule com-
pounds to bind.23-25 The interface area of the interaction is
In spite of these obstacles, progress is being made. In recent
years, some PPI modulators have entered clinical studies;
some have been approved for marketing, indicating that the
modulators targeting PPIs may have broad prospects. In
comparison with peptides targeting PPIs, small-molecular
inhibitors of PPIs are increasingly appealing, because these
drugs tend to have lower research costs, oral preparations,
and better tumor microenvironment penetration.
Inhibitors of MDM2/p53 interaction (small molecules,
peptides) p53 regulates the cell cycle and functions as
a tumor suppressor. Almost 50% of human cancers have
alterations in the TP53 gene, which results in the in-
activation of p53 function or loss of p53 expression.29 The
MDM2 protein is the p53 E3 ubiquitin ligase that, under
cellular stress conditions, ubiquitinates p53 and facilitates
p53 nuclear export and inhibition of transcription activity
or ubiquitin-dependent proteasomal degradation of p53.

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 Taking Aim at the Undruggable
Utilizing small molecules or peptides to block the p53/
MDM2 interaction is one way to restore the p53 pathway in
wild-type p53 tumors, thereby preventing the inactivation of
p53. Nutlins are the most well-characterized small mole-
cules that disrupt this p53-MDM2 interaction, binding to the
N-terminal pocket of MDM2 and stabilizing p53, which
helps to retain tumor-suppressive functionality. There is
extensive in vitro and in vivo evidence to demonstrate that
nutlins increase p53 levels and apoptosis, as well as de-
crease tumorigenicity.30
Building on this momentum, the nutlin derivative RG7112
has advanced to clinical trials for leukemia and sarcomas
along with a number of other small molecules with similar
mechanisms of action that are currently in phase I clinical
trials, including SAR405838, CGM097, HDM201, DS-
3032, MK-8242, and AMG232.31-33 Thus, there is consid-
erable clinical interest and activity focused on inhibiting
p53-protein interactions using small molecules. Another
target being modulated by the use of PPI is the interaction of
MLL1 and menin. Once the crystal structure of menin was
available, the binding site with MLL became clear; currently,
drugs such as KO-539 show promising clinical activity in
refractory acute myeloid leukemia.34
Other Approaches Using Small Molecules
An indirect approach to targeting challenging and difficult
targets is the search for “synthetic”35,36 and “collateral”37
lethality scenarios. In synthetic lethality, cancer-specific
mutations that impair the function of one gene (e.g.,
BRCA1) can be exploited with pharmacologic inhibition of
another key component of the pathway (e.g., inhibiting
PARP with olaparib), which would lead to the death of
cancer cells with the genetic mutation but spare normal
cells that lack the genetic vulnerability. In addition to the
approval of many PARP inhibitors for the management of
BRCA1/2 ovarian and breast cancers, current clinical trials
are exploring this paradigm by using these agents in tumors
with alterations in other DNA-repair enzymes, such as
PALB2, ATM, and RAD51. Synthetic lethality is also ob-
served in tumors bearing mutations in the SWI/SNF chro-
matin remodeling complexes (e.g., SMARCA2, SMARCA4,
ARID1A, and ARID1B); tazemetostat, an EZH2 inhibitor,
has recently been approved by the U.S. Food and Drug
Administration for the management of malignant rhabdoid
tumors, a disease driven by SMARCA4 mutations.
The term “collateral lethality” is preferred to synthetic le-
thality when a “passenger” gene mutation (alteration not
playing an active role in tumor progression) is lost along with
an adjacent oncogenic or “driver” alteration (in our case, an
undruggable tumor-suppressor gene). Using the lack of
function of passenger-deleted genes for a therapeutic ad-
vantage could exploit cancer-selective vulnerabilities. Such
is the case with MTAP, a gene that is frequently codeleted
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with CDKN2A (cyclin-dependent kinase inhibitor). MTAP-
null cancer cells seem to have a dependency on PRMT5 (a
methyltransferase); therefore, inhibition of PRMT5 could be
exploited for cancer treatment. In fact, PRMT5 inhibitors are
in clinical development.38 Based on this hypothesis, MTAP/
CDKN2A-null tumors could be sensitive to PRMT5 inhibitors
while normal cells are spared, offering a wide therapeutic
window. Other examples of this paradigm include the 1p36
deletion (which includes tumor-suppressor genes, such as
CAMTA1, mir34A, or KIF1B), the passengers enolase 1 or 6-
phosphogluconate dehydrogenase, and the therapeutic
inhibition of enolase 2 or components of the nonoxidative
pentose phosphate shunt.39
Another way to modulate an undruggable protein with small
molecules is to modulate its transcription levels: either in-
directly, by targeting chromatin regulation, or directly, by the
targeting of transcription factors or RNA that regulates its
expression. There are ongoing drug-discovery efforts fo-
cusing on small-molecule drugs targeting transcription
factors, such as P53, MYC, and STAT3. These transcription
factors, which are frequently altered in cancer, form protein
complexes that are directed to specific sites on DNA and
regulate oncogenic events. Small molecules interacting with
MYC, STAT3, or P53 are in development. These agents
mostly aim to prevent the formation of these multiprotein
complexes, rather than to disrupt the transcription factor–
DNA interaction.2
Targeting chromatin regulation, the main goal of epige-
netics, has also seen tremendous development with the
expansion of technologies that allow analysis of the epi-
genome and drug discovery now aiming for new targets,
such as EZH2, LSD1, PRMT inhibitors, and others. How-
ever, the field of epigenetics drug development is beyond
the scope of this review and can be found elsewhere.40
There is a conventional view that it is not possible to bind
RNAs with small molecules because they present unrelated
structures and complex pockets for druggability (RNA
interference–based therapeutics are discussed in the next
section). However, it has since been discovered that RNA
molecules actually adopt secondary and tertiary structures
that could be attractive targets for small molecules. In fact,
many drugs, including several antibiotics (e.g., amino-
glycosides) bind bacterial RNA in the ribosomes. This field
changed in 2020, when the U.S. Food and Drug Admin-
istration approved risdiplam, an SMN2-splicing modifier, to
treat spinal muscular atrophy. This is the first drug designed
specifically against a particular messenger RNA (it modifies
the splicing of SMN2 messenger RNA, resulting in an in-
crease in the concentration of the functional SMN protein
in vivo).41 The development of anticancer small molecules
that specifically bind RNA, although still in its early stages,
aims to design similar small-molecule RNA modulators that
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 Coleman and Rodon
bind RNA molecules and change protein synthesis by
modifying RNA processing (RNA splicing) or impeding
protein production.42
NEW BIOLOGICS CAN ALSO ENABLE THE IMPOSSIBLE
Despite efforts to modulate RNA and protein expression with
small molecules, described above, biologic molecules, such
as antisense technologies, have remained the most com-
monly deployed method to target disease-associated RNAs.
First-generation oligonucleotide structures had poor cell
permeability and distribution and triggered immunoreac-
tivity; as a result of their poor pharmacology, their devel-
opment languished for years. Now, these initial problems of
RNA therapeutics have been addressed with improvements
in trigger design, sequence selection (to avoid unintended
off-target RNA interference effects), chemical formulation
(to avoid degradation by endonucleases and exonucleases),
and delivery mechanisms (lipid nanoparticles and others),
enabling a second generation of drugs. Consequently, in
2018, the U.S. Food and Drug Administration approved
patisiran, a small interfering RNA for the treatment of he-
reditary transthyretin amyloidosis with polyneuropathy.
Since then, two more drugs of this kind, lumasiran and
givosiran, have been approved. Patisiran, which primarily
acts on the liver, is not a metabolically stabilized small
interfering RNA, but it uses a lipid nanoparticle delivery
formulation. More recently, small interfering RNA thera-
peutics have been metabolically stabilized to improve their
stability.
However, not all RNA transcripts transmit a message for
protein coding and translation, but there is a diverse range of
noncoding RNA molecules (e.g., long noncoding RNAs,
microRNAs, small nuclear and small nucleolar RNAs) with
broad roles in modulating gene expression, including
cancer deregulation. Because of recent developments in
the field, RNA therapeutics are not limited to antisense
oligonucleotides; investigators are exploring small in-
terfering RNA, microRNA, messenger RNA, RNA aptamers,
short activating RNA, and single guide RNA for CRISPR/
Cas9 systems as potential therapeutic platforms. Some of
these novel RNA therapeutics are also aiming for some
undruggable targets that are relevant in cancer, such as
EWS/FLI1 (Ewing sarcoma), KRAS G12D (pancreatic can-
cer), miR-155 (lymphoma and leukemias), and miR-16
(malignant pleural mesothelioma and non–small cell lung
cancer).
One final approach using biologics to target complicated
intracellular targets involves the TCR-HLA (human leuko-
cyte antigen) system. The target, processed in the immu-
noproteasome, is broken into different peptides that are
presented by the tumor cell’s HLA system to the immune
system via the TCR; this interaction activates the immune
system against the tumor cell. Antigens that can be
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leveraged for this approach include those arising from
cancer mutations (e.g., in otherwise undruggable proteins),
known as neoantigens, and tumor-associated antigens,
which result from overexpressed genes. This principle,
which is the basis for modern cell therapy (e.g., CAR T cells,
engineered TCR therapy) is now also being replicated by
different types of peptides (TCR “mimetics”)43: TCR-like
antibodies and TCR fusion proteins. These TCR mimetics
are advantageous in that they can have more drug-like
properties and avoid some of the limitations of traditional
cell therapies (e.g., prolonged and expensive production
times, cost). In addition to CD19, which was the first target
for leukemias (tisagenlecleucel, the first CAR T-cell therapy
was approved for acute lymphoblastic leukemia in 201744),
in solid tumors, initial research with cell therapy and TCR
mimetics initially focused on tumor-associated antigens,
such as GP100, MAGEA4, NYESO1, and PRAME; the first
generation of studies is ongoing. Theoretically, neoantigen-
specific CAR T cells or TCR mimetics (antibodies or soluble
TCRs) that are specific for the peptide–major histocom-
patibility complex could be a promising strategy to tackle
repetitive mutated variants in undruggables, such as fusion
peptides in sarcoma (breakpoint-specific neoantigens have
been predicted and validated, in part, for EWSR1-FLI1,
PAX3-FOXO1, and SS18-SSX1)45,46 or KRAS in pancreatic
cancer.47
The clinical proof of concept for cell therapy came from
targeting CD19.48 For TCR mimetics, this has likely been
achieved with the recently presented data on tebentafusp
(IMCgp100) that showed clinical benefit, including target
lesion reduction.49 Tebentafusp is a solution of soluble TCRs
stabilized by a disulfide bond and fused to an anti-CD3 scFv
(a so-called “ImmTAC molecule”). Early data from a phase II
trial in patients with HLA-A*0201+ gp100+ metastatic uveal
melanoma showed that, although the overall response rate
by response evaluation criteria in solid tumors was low (5%),
it was accompanied by a reduction in target lesion in 44% of
patients. The median overall survival was 16.8 months
(95% CI, 12.9–21.3), which seems promising compared
with historical controls.50
CONCLUSION
There is considerable excitement surrounding the devel-
opment of cancer targets considered undruggable, with
classic classes of agents, including transcription factors,
such as STAT3, TP53, MYC. Others, like RAS (KRAS G12C
and HRAS), HIF-2α, BCL-2, MDM2, and MLL, are now
validated druggable targets.
Because of the possibility that many other pharmacologic
barriers might be overcome by the new entities described
here, the concept of undruggable is being challenged, and
some now consider it an inappropriate or démodé term. In
the presence of novel molecular entities that promise to
 Taking Aim at the Undruggable

become game changers, some advocate for using terms ACKNOWLEDGMENT

such as “undrugged,” “difficult-to-drug targets,” or “targets Editorial assistance was provided by Dr. Paul Fletcher and
with developability challenges” rather than undruggable. Daley Drucker (Moffitt Cancer Center’s Scientific Editing
Time, and the efforts of a new generation of drug de- Department). No compensation was provided beyond their
velopers, will tell. regular salaries.

AFFILIATION Holcombe Blvd., FC8.3052, Houston, TX 77030; email: jrodon@

Division of Cancer Medicine, Department of Investigational Cancer
Therapeutics, The University of Texas MD Anderson Cancer Center,
Houston, TX
CORRESPONDING AUTHOR
Jordi Rodon, MD, PhD, Department of Investigational Cancer
Therapeutics, The University of Texas MD Anderson Cancer, 1400
mdanderson.org.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/10.1200/
EDBK_325885.

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