SATUAN

ACARA PENGAJARAN

MATAKULIAH : DASAR-DASAR FARMAKOLOGI MOLEKULER

KODE/SKS : 2 SKS
SEMESTER :VI
PERTEMUAN : 11
DOSEN : BESSE HARDIANTI,M.Pharm.Sc,Apt.
MATERI :RESEPTOR TIROSIN KINASE SEBAGAI
TARGET AKSI OBAT

SEKOLAH TINGGI ILMU FARMASI (STIFA)

MAKASSAR
2016
RESEPTOR TIROSIN KINASE SEBAGAI TARGET AKSI OBAT
KompetensiUtama : Mampu dalam penguasaan dan menguasai
pemahaman konsep teoritis dan menjelaskan tentang mekanisme aksi obat
dalam tubuh pada tingkat molekuler yaitu transduksi signal dan mekanisme
aksi obat pada berbagai target aksi obat
KompetensiPendukung : 1. Memiliki penguasaan dan keterampilan bidang
bahasa asing dan teknologi informasi.
2. Mampu mengembangkan diri dalam
pengembangan obat dan sediaan bahan alam.
Kompetensi Lainnya : Mampu untuk memotivasi dan memfasilitasi
masyarakat.
Sasaran Belajar (TIU) : Mampu menjelaskan dan memahami
Mekanisme kerja obat pada Reseptor Tirosin
Kinase sebagai Target Aksi Obat
Materi Pembelajaran : Ligan yang berperan pada Reseptor
Tirosinkinase
Mekanisme transduksi Signal pada interaksi
ligan dengan reseptor Tirosin Kinase
Aksi Obat pada Reseptor Faktor Pertumbuhan
(Growth Factor), Reseptor Sitokin (Cytokine
receptor), dan Reseptor Insulin

Dosen : Besse Hardianti,M.Pharm.Sc.,Apt

Farmakologi Molekuler
Presenter Name Besse Hardianti
Presentation Date 17 desember 2015

Tyrosine Kinase
•  Is an enzyme that can transfer a phosphate group
from ATP to a protein in a cell.

•  It functions as an "on" or "off" switch

in many cellular functions.

•  The phosphate group is attached to the

amino acid tyrosine on the protein.

2

Key points

1.  Even though cancer cells are complex, they may be

addicted to one or a few key pathways ( oncogene
addiction ), often driven by an RTK.
2. Some RTKs are validated or very promising as
therapeutic targets. Particularly for tumors with
oncogene addiction .
3. We are testing RTK inhibitors in the clinic. Some work
well for some diseases.
4. Resistance to RTK inhibitor may arise through several
different mechanisms. Understanding these
mechanisms of resistance is important for designing
better combination therapies.

Tyrosine Kinase Types

1.  Receptor tyrosine kinases
eg: EGFR, PDGFR, FGFR

2.  Non-receptor tyrosine kinases

eg: SRC, ABL, FAK and Janus kinase

6

Targeted Therapy
•  is a type of medication that blocks the growth of cancer
cells by interfering with specific targeted molecules needed
for carcinogenesis and tumor growth.

•  rather than by simply interfering with all rapidly dividing

cells (e.g. with traditional chemotherapy).

Tyrosine Kinase Inhibitor

1.  BCR-ABL Tyrosine Kinase Inhibitors
eg: Imatinib, Dasatinib, Nilotinib.

2.  Epidermal Growth Factor Receptor

Tyrosine Kinase Inhibitors
eg: Gefitinib, Lapatinib.

3.  Vascular Endothelial Growth

Factor Tyrosine Kinase Inhibitors
eg: Semaxinib, Vandalinib,
Sunitinib, Sorafenib.

8

 9

Is a pharmaceutical drug that inhibits tyrosine kinases.

They are also called Tyrphostins, the short name for “tyrosine
phosphorylation inhibitor”, originally made in 1988 ,which was
the first description of compounds inhibiting the catalytic
activity of the epidermal growth factor receptor (EGFR).

The 1988 study was the first demonstration of a systematic

search and discovery of small molecular weight inhibitors of
tyrosine phosphorylation, which do not inhibit protein kinases
that phosphorylate serine or threonine residues and can
discriminate between the kinase domains of the EGFR and that
of the insulin receptor.

TKIs operate by four different mechanisms:

1.  They can compete with adenosine triphosphate

(ATP),
2.  The phosphorylating entity,
3.  The substrate or both or
4.  Can act in an allosteric fashion, namely bind to a site
outside the active site, affecting its activity by a
conformational change.

Signal transduction therapy can in principle also apply

for non-cancer proliferative diseases and for
inflammatory conditions.

Tasigna

 It is FDA- (29 October 2007) for use as a treatment for
Philadelphia Chromosome (Ph+)-positive Chronic myelogenous
leukaemia.

In June 2006, a Phase I clinical trial found nilotinib has a

relatively favorable safety profile and shows activity in cases of
leukemia resistant to treatment with imatinib, another tyrosine
kinase inhibitor currently used as a first-line treatment.

In that study 92% of patients (already resistant or unresponsive

to imatinib) achieved a normal white blood cell counts after five
months of treatment.
in this setting.

The drug carries a black box warning for possible heart

complications.

The use of low doses of nilotinib is being investigated for

use for Parkinson's and Alzheimer's disease, as well as for
dementia and Huntington's disease.

Novartis announced on April 11, 2011 that it is

discontinuing a Phase III trial of Tasigna (nilotinib) for
investigational use in the first-line treatment of
gastrointestinal stromal tumor based on the
recommendation of an independent data monitoring
committee.

 Nilotinib is a tyrosine-kinase inhibitor. Nilotinib binds to and stabilizes the
inactive conformation of the kinase domain of Abl protein.

In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine

leukemic cell lines and human cell lines derived from patients with Ph+
CML.

Under the conditions of the assays, nilotinib was able to overcome imatinib
resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33
mutations tested.

In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft

model.

Nilotinib inhibited the autophosphorylation of the following kinases at IC50

values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM), c-Kit (210 nM),
CSF-1R (125-250 nM) and DDR (3.7 nM).

Imatinib (Gleevec)
•  MOA:
Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal gene product of the
Philadelphia chromosome in chronic myeloid leukemia (CML).

•  Indication:
Ph+ CML
Ph+ ALL
GIST

website:
http://www.gleevec.com/index.jsp
16

 Imatinib (Gleevec)
Toxicity:
•  Cardiovascular: Edema/fluid retention (11% to 86%)
•  Central nervous system: Fatigue (29% to 75%), pain (≤47%), fever (6% to 41%), headache
(8% to 37%), dizziness (5% to 19%)
•  Dermatologic: Rash (9% to 50%), dermatitis (GIST ≤39%), alopecia (GIST 10% to 15%)
•  Endocrine & metabolic: LDH increased (GIST ≤60%),
•  Gastrointestinal: Nausea (42% to 73%; Ph+ ALL), diarrhea (25% to 59%; Ph+ ALL),
vomiting (11% to 58%), abdominal pain (3% to 57%), anorexia (≤36%), weight gain (5% to
32%),
•  Hematologic: Anemia (25% to 80%), leukopenia (GIST 5% to 47%), hemorrhage (3% to
53%), neutropenia (12% to 16%)
•  Hepatic: Transaminases and/or bilirubin increased (57%)
•  Neuromuscular & skeletal: Muscle cramps (16% to 62%)
•  Ocular: Periorbital edema (29% to ≤74%)
•  Renal: Serum creatinine increased (≤44%)
•  Respiratory: cough (11% to 27%), upper respiratory tract infection (3% to 21%)
•  Miscellaneous: Infection (Ph+ ALL 53%; GIST ≤28%) 17

Dasatinib

•  MOA:
BCR-ABL tyrosine kinase inhibitor; targets most imatinib-resistant BCR-ABL
mutations.

•  Indication:
Ph+ CML
Ph+ ALL

website:
https://www.sprycel.com/index.aspx

18

 Dasatinib

Toxicity:
•  Cardiovascular: Fluid retention (21% to 35%)
•  Central nervous system: Headache (12% to 33%), fatigue (8% to 24%), fever (5% to 18%)
•  Dermatologic: Rash (11% to 21)
•  Endocrine & metabolic: Hypophosphatemia (5% to 18%)
•  Gastrointestinal: Diarrhea (18% to 31%), nausea (9% to 24%), vomiting (5% to 16%), abdominal
pain (3% to 12%)
•  Hematologic: Thrombocytopenia (19% to 85%), neutropenia (22% to 79%), anemia (11% to 74%),
neutropenic fever (1% to 12%)
•  Neuromuscular & skeletal: Musculoskeletal pain (≤19%)
•  Respiratory: Pleural effusion (12% to 24%)
•  Miscellaneous: Infection (9% to 12%)

19

Gefitinib

•  MOA:
Gefitinib is a tyrosine kinase inhibitor (TKI) which inhibits numerous tyrosine
kinases associated with transmembrane cell surface receptors found on both
normal and cancer cells, including the tyrosine kinase associated with the
epidermal growth factor receptor, EGFR.

•  Indications:
Non-small Cell Lung Cancer (NSCLC)
Monotherapy for continued treatment of locally advanced or metastatic
NSCLC after failure of both platinum-based and Docetaxel regimens

•  website
http://www.iressa.com

20

Gefitinib

Toxicity
•  Dermatologic: Rash (43% to 54%), acne (25% to 33%), dry
skin (13% to 26%), paronychia (14%)
•  Gastrointestinal: Diarrhea (48% to 67%), nausea (13% to
18%), vomiting (9% to 12%)

21

Lapatinib

•  MOA:
Tyrosine kinase (dual kinase) inhibitor; inhibits EGFR (ErbB1) and HER2 (ErbB2).
Combination therapy with lapatinib and endocrine therapy may overcome endocrine
resistance occurring in HER2+ and hormone receptor positive disease.

•  Indications:
Metastatic Breast Cancer in combination with Capecitabine in patients whose tumors
overexpress HER2 and who have received prior therapy including an Anthracycline, a
Taxane, and Trastuzumab.

website
http://www.tykerb.com/

22

Lapatinib
Toxicity
•  Central nervous system: Fatigue (10% to 20%), headache (≤14%)
•  Dermatologic: (hand-and-foot syndrome) (with capecitabine: 53%), rash (28% to 44%),
alopecia (≤13%)
•  Gastrointestinal: Diarrhea (64% to 65%), nausea (31% to 44%), vomiting (17% to 26%),

•  Hematologic: Anemia (with capecitabine: 56%), neutropenia (with capecitabine: 22%)

•  Hepatic: total bilirubin increased (22% to 45%)
•  Neuromuscular & skeletal: weakness (≤12%), back pain (≤11%)
•  Respiratory:Dyspnea (≤12%)

23

Sorafinib

•  MOA:
Multikinase inhibitor; inhibits tumor growth and angiogenesis by inhibiting intracellular
Raf kinases, and cell surface kinase receptors (VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-beta, cKIT, FLT-3, and RET).

•  Indications:

Treatment of advanced renal cell cancer (RCC); treatment of unresectable hepatocellular

cancer (HCC)

website
http://www.nexavar-us.com/scripts/pages/en/patient/index.php

24

 Sorafinib

Toxicity
•  Cardiovascular: Hypertension (9% to 17%)
•  Central nervous system: Fatigue (37% to 46%),
•  Dermatologic: Rash (19% to 40%), hand-foot syndrome (21% to 30%), alopecia (14% to
27%)
•  Endocrine & metabolic: Hypoalbuminemia (≤59%),
•  Gastrointestinal: Diarrhea (43% to 55%), weight loss (10% to 30%),, nausea (23% to
24%), vomiting (15% to 16%), constipation (14% to 15%)
•  Hematologic: Lymphopenia (23% to 47%),
•  Hepatic: Liver dysfunction (≤11%)
•  Neuromuscular & skeletal: Muscle pain, weakness
•  Respiratory: Dyspnea (≤14%), cough (≤13%)

25



Contoh metode penemuan mekanisme dari senyawa murni yang
diperoleh dari tumbuhan





Chemical structure and biological properties of piperine

Pepper longa

Biological properties of piperine

ü  A n t i - i n f l a m m a t o r y activity
ü  A n t i - d e p r e s s a n t activity
ü  A n t i - a r t h r i t i c a c t i v i t y
Ahmd Sherif ü  E n h a n c e r o f b i o a v a i l a b i l i t y

 Piperine potentiated the TRAIL-induced cytotoxicity in a
concentration dependent manner

Cell viability assay

TRAIL-resistant TRAIL-sensitive
MDA-MB-468 MDA-MB-231

Piperine potentiated the TRAIL-induced
Caspase 3 and PAPR cleavage

Spreading Piperine TRAIL

of cells (50 ng/ml)

24 h 30 min 3 h Western
blot

TRAIL-resistant TRAIL-sensitive
MDA-MB-468 MDA-MB-231

Apoptotic
markers

poly ADP ribose polymerase (PARP)

 Drug Interactions
Strong CYP3A4 Inhibitors:
ketoconazole, itraconazole, voriconazole, posiconazole
clarithromycin, telithromycin
atazanavir, indinavir, nelfinavir, ritonavir, saquinavir,
nefazodone

Moderate CYP3A4 Inhibitors:

fluconazole, erythromycin, aprepitant, grapefruit juice,
verapamil, cimetidine

29

SUMMARY
•  Targeted therapy provides a new approach for
cancer therapy that has the potential for avoiding
some of the drawbacks associated with cytotoxic
chemotherapy
•  At the present time, tyrosine kinase inhibitors serve
more as second- or third-line therapies rather than
as primary therapy.
•  For the tyrosine kinase inhibitors to have a primary
role in therapy, there has to be a clear hypothesis
for their use, relevant preclinical data, and a
demonstrated use in well characterized groups of
patients

 REFERENCES

1.  Goodman & Gilman s The Pharmacological Basis

of THERAPEUTICS. Twelfth edition: pg
1731-1740
2.  Bertram G,Katzung,Basic & Clinical Pharmacology,
eleventh edition: pg 953-955.
3.  Charles R.Craige, Robert E.Stitzel: MODERN
PHARMACOLOGY with Clinical applications.pg
653.
4.  Lippincott s Illustrated Reviews:Pharmacology 5th
edition:pg 509-511.

REVIEW ARTICLES
1.  Amit Arora and Eric M: Role of Tyrosine Kinase
Inhibitors in Cancer Therapy , THE JOURNAL OF
PHARMACOLOGY AND EXPERIMENTAL
THERAPEUTICS [JPET] 315:971–979, 2005.
2.  Jianming Zhang- Targeting cancer with small
molecule kinase inhibitors : Nature Rev. Drug Discov
January 2009 | Volume 9: 28-39.

 Contoh soal

A. Tipe Soal ISIAN

(1)……… termasuk golongan obat penghambat BCR-ABL tirosin kinase,
sementara penghambat reseptor epidermal growth factor adlah (2)…… dan
(3)….., Gleevec adalah obat dengan target aksi pada reseptor tirosin kinase yang
digunakan untuk terapi penyakit (4)……….. sementara Sorafinib ditujukan untuk
ec) terapi penyakit (5)…….

B. Tipe soal ESSAI

1. Tuliskan dan jelaskan perbedaan antara sel normal dengan sel kanker.
se, the constitutive abnormal gene product of the
2. Tuliskan 4 mekanisme dari penghambat tirosin kinase(TKI)
chronic myeloid leukemia (CML).
3. Jelaskan mekanisme kerja Imatinib berdasarkan gambar dibawah ini

4. Tuliskan dan jelaskan mekanisme kerja, Indikasi dan toksisitas dari Gefitinib
sp 5. Jelaskan salah satu metode penemuan mekanisme kerja obat piperin

16