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    9 views52 pages

    US2022023301A1 Original Document 20230501142310

    Uploaded by

    David Nguyen

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    © All Rights Reserved
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    of 52
    Us 202200233 ca») United States OAL c2) Patent Application Publication co) Pub. No.: US 2022/0023301 Al Ouk et al. (43) Pub, Date: Jan. 27, 2022 (64) METHODS OF TREATING AUTOIMMUNE, DISEASES WITH SMALL MOLECULE, NE-KB INHIBITORS (71) Applicant: ImmuneTurget, Ine, Medina, WA (US) (72) Inventors: Samedy Ouk, Medina, WA (US): Hsiou-Chi Liou, New York, NY (US) (73) Assignee: ImmuneTarger, Inc., Medin, WA (US) (21) Appl. No 177384,661 (22) Filed: Sul 23, 2021 Related US. Application Data (6) Provisional application No, 631087,167, filed on Jul 27, 2020. Publication Classification (51) Im cl. AIK 31519 (2006.01) ‘ALP 37106 (2006.01) (2) USC. cre AGIK 31/519 (2013.01); AGIP 3706 2018.01) on ABSTRACT The present invention provides, inter alia, compounds capable of inhibiting NF-kB. Pharmaceutical compasitions containing and methods of using the compounds are also provided here, Also provided are compositions, methods ‘and kis for treating autoimmune diseases, including but not limited to rheumatoid anhitis, multiple sclerosis, systemic lupus erythematosus, all comprising andor utilizing the [NF-KB inhibitors described herein. 12 Zz 10 ie ey 8+ i 7 32 gl ao i 3 4 5 o 2 0 500 1000 c-Rel protein 10 nM CD28RE FITC FP assay ea ns a oF —+-Si/B . ebook - . _ - _ _ 2 1500 2000 concentration (nM) 2500 US 2022/0023301 Al Jan. 27, 2022 Sheet 1 of 7 Patent Application Publication o1Dla avo | BS Aossy a4 941s-3uezaD WU EEO ones punaseyaeqneutis 1 [sepnsronvobee pega oo Ge jaseseeaRree ‘)vonmmantentees Errore Poe uneasy pones8y20q jug at‘DLL VIO Patent Application Publication Jan. 27, 2022 Sheet 2 of 7 US 2022/0023301 Al ‘compound in example 6 Concentration Rel/NF-KB inhibition by compound 6 by EMSA 120 xodiuos ainzag-14 % US 2022/0023301 Al Patent Application Publication Jan. 27, 2022 Sheet 3 of 7 quounealy Joyy skeq WEeLZuO es LaSvezeo dd By/6wz'9 xeq Zdnoig -«~ dig By/Buog ejo1 gdnoig -e- ig By/6u9's sps-Lisdnoip ~~~ dig Sy/bug'z epe-Li drop ~~ Gia 6y/fugz"1 ere-Li ednosy -*- BOE, ZdnoI ~~ [EWUON |dnos -e~ qBbiam Apog 1yBIem s,Apog jewjuy WWE “BIA (6) uBjem Apog US 2022/0023301 Al Jan. 27, 2022 Sheet 4 of 7 Patent Application Publication jyusugjealy sayy sheg PLEeLzcLtLOLé6 BLOGevPETEODA do 6y/6uz"0 xeq Zdno ig 6y/6wo¢ e301 gdno.p dig 5y/6wo0's ere-LI sdnosp dig Sy/6ug 2 ere-L1 pdnop Gig Sy/Gwgz"L ere-LI ednosp aoryen zdno TeWJON dno i4t ett abueys yybiem Apog yyBiem s Apog jeuiue ul ebueyo° ge Big (%) aBueys zyBjam Apog US 2022/0023301 Al Jan. 27, 2022 Sheet 5 of 7 Patent Application Publication yuougeal sayy skeq vLELTLELOLG BL9GwrEZEO CO ByGwuz'9 xe Zdnoip aig S4/Bup¢ eo gdnoip aig 5y/Bu0's ¢b8-LI sdnoip, aia 6y/Bug7% syB-LI pdnoiD aig 6y/Bugz"1 eve-Li ednop aren zdnoig TeuoN |dnoss Peet tae aioos snuuLy Joos Jeoluljo SHUYLY ployeuneyy tp Bid [e0}-81098 SHU US 2022/0023301 Al Patent Application Publication Jan. 27, 2022. Sheet 6 of 7 quewjeas) sayy skeq werzbboLeé BL9SHEZLO dO 6y/6wz'0 xeq sdnoIp ~«- ala By/Buige ej) gdnoig -=- aig 64/Bwi9's gp8-11 Gdnoig ~~ aia By/Bug'Z sv8-L| ydnoiD ~«- dd By/Bug Zz sy8-Li ednoig ajueA Zdnosd ~s- Teuion LdnoJg -e- @UINJOA Med SUUINJOA Med jeWIUY WE Big (71u) eunjoa Meg US 2022/0023301 Al Jan. 27, 2022 Sheet 7 of 7 Patent Application Publication dd 6y/6uz"0 xed Zdnaip Gig By/Buiog ej) gdnoip, ig 64/Bw9's gye-11 Gdnoig aig By/Bug'z gye-11 pdnoig dig S6usz"L syg-Li ednoip aja1yan Zdnosg feuoN }dnosp (oAep-p_Aep)auinjoa med eyoq ewunjoa med eyeq- gg Big 3 8 o ofep-pLAep (1w) eunjoa med ‘Oro US 2022/0023301 Al METHODS OF TREATING AUTOIMMUNE, DISEASES WITH SMALL MOLECULE NF-KB INHIBITORS (CROSS.REFERENCE TO RELATED "APPLICATIONS. [0001] This application claims priority to U.S, Provisional Application Set. No. 63/057,167, fled Jul. 27, 2020, the disclosure of which is herchy incorporated by reference FIELD OF INVENTION 10002] The present invention provides, inter alia, com- ‘pounds and pharmaceutical compositions capable of ihib- iting NF-xB, as well methods of using said compounds to ‘real autoimmune diseases nd compositions. BACKGROUND OF THE INVENTION NP-&BIRel [0003] _NF-KFVRel (nuclear factor kappa B) is a family of transcription factors that includes pS0‘p105 (NF-xB1), p52/ (p100 (NF-KB2), p65 (RelA), c-Rel, and RelB. These mol- ecules can homo- of heterodimerize: and are generally sequestered inthe cytoplasm by their inhibitors, IKBS. Upon ‘activation, IkBs are degraded by the 26s proteasome and |NF-xB limers migrate into the nucleus 1 perform tanserip- tional activity [0004] -NE-KEB (pS0\p65) and c-Rel are regulated by the canonical IKK iB kinase complex. pathway, whereas RelB and $2 (NF-xB2) are regulated by an altemative pathway via the IKKe/NIK complex. Despite this similarity, ‘each NF-xB family member i distinct with regard to tissue ‘expression pattem, response fo receptor signals, and target ‘gene specificity. These differences are evident from the ‘non-redundant phenotypes exhibited by individual NF-xBY Rel knockout mice, Therefore, therapeutics targeted to dlif= fereat NF-xB/Rel members are likely to have different biological ellects and toxicity profiles, [0005] Many receptors aad stimuli can activate NF-xB/ Rel, including TCR/BCR, TNF receptor superfamily (e- ‘CD¢O, TNFRL, TNFR2, BAFF, APRIL, RANK), IL-1/TLR receptors, and’ Nod-like receptors, as well as sctivating ‘oncogenes (e.g. See, Ras, LMP-I, Tax, v-FLIP), reactive ‘oxygen radicals, radiation, and chemotherapeutic agents. In response to these stimuli, NF-xB/Rel regulates the expres- sion of cytokines, chemokines, and molecules that play a role in adhesion, the eelleyele, spoptoss, immune modu lation, and angiogenesis. As such, NF-KBRel trnseription facors are important therapeutic targets for many human disorders, including inflammation, autoimmune diseases, ‘and cancer, and small molecule inhibitors of NF- ules were more likely to contain genes with bona fide susceptibility varin's. In particular, the sty identified Several high-eonfidence candidates Gnchuling BCL, CD48, REL, TRAF3, and TEC) [Intemational Multiple Sclerosis Genetics Consoaium, dim J. Ham. Genet. 2013, 92, 854-865]. [0014] Condiionl knockout-mice for IxBe in myeloid cells (ysMCrelxBa(@/M)) have been generated and are characterized hy a constntive atvation of NF-KB proteins allowing the study of this transcription factor in myelin- oligodendrocyte-glycoprotein induced experimental autoim- mune encephalomyelitis (MOG-EAE), a well-established experimental model for autoimmune demyelination of the CNS. Compared to controls, lysMCrelkBa(fl/fl) mice devel- oped a more severe clinical course of EAB. In addition, lysMCreIkBa(ill) mice displayed an increased expression of the NF-xB dependent factor inducible nic onide sy those in named lesions. These changes in the CNS are associated with intend numbers of CDT positive sple- US 2022/0023301 Al nocytes and ahigher expression of Ly6e on monocytes ia the periphery In aeordance with these changes inthe myeloid cell compartment, thee was an ineressed production of the mongeyte eytokines interleukin (IL)-12 p70, IL-6 and IL-Ibetainsplenoeyes. By const, pructiono the Fell sociated cytokine interferon gamma (IFN-gamma) and IL-7 was not affected. In summary, myeloid cell derived NF-kB plays a eri tole in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and ‘macrophages independent of cells (G. Elkichman etl ‘Neuronflanmation 2012, 9:15} {0013} In ight of genetic evidence from a large cohort of IMS patients and the development of EAE in ysMCrelxBsa (Oi) mice, we believe that inhibition of ReV/NF-KB has poteail to manage MS symptom, prevent further damage to myelin, and repair myelin shoot. deed, natural proct “riploide, an NF=eB inhibitor, 0.128 malkg administered intaperitoncally diy. improves motor funtion and motor coordination compared. 10 control group in cuprizne induced neuronflammation mouse model. It appears that triple at 0.125 markg dose was abe to rase the number of OLGs precursor cells (NG-2"104"), raluce Baw Bel rato, and improve behavioral defies (N. Sanadgol eta Taxico, Appl. Pharmacol. 218, 842 86. [0016] REINE-KB as Drug Target for Systemic Lupus Enythematosus (SLE) [0017] Systemic lupus erythematosus (SLE) isa chronic sutoismue disease characterized by eaul-orga iilam- tin, resting from los of tolerance to sel-antigens and production of antinuclear antibodies. These antibody clear antigen complexes drive inflammation in multiple ‘organs inching the kidney, resulting in sue damage. Kis thought that meleic act-immune complexes activate the inate immune tesponse trough Toll-like receptors (TLR) 7 and 9 in plasmacytoid dendritic cells (pDIC) and other cell |ypes, diving production of type Interferon, The resulting interferon signature metic not only coreelstes with SLE disease severity in human patient, but also promotes dis- ‘tse, as blockade of type I interferon signaling through niffolamab has shown promising elcacy in phase Tl clinical ri [0018] In ation to TLR and type 1 interferon (IFN), Several tumor necrosis fictor (TNE) recepor superfamily CINFRSF) members ae implicated in SLE athophysiol- ‘gy. B cll activating factor (BAFF) and CD40 are required for B cell survival and dillerentition to auto-anibody- prodocing plasma cells. Blockade of CD40 ligand (CD40L) Showed promising eects in erly lupus clinical als, even though development was halted dive t thrombotic side cles, On the other hand, BAFF blockade through beim ‘uma is partially eficacions and is the only new therapy for Tupos approved in more than 50 year (H.D. Briahtbil et al Nature Comm, 2018; 195179] [R.K. Mishra Nephrol Open J. 2016; 21) 9-13} [0019] Notably, nuclear NF-KB is highly oetvaed by the ‘sforementioned signaling pathways inching TLR7, TLRS, (CD40, and BAFF, during SLE pathogenesis. To investigate the ole of NF-kB family membors NF-IkBI, NF-xB2 and e-REL in SLE. L. A. O'Reily et a. wenerated Fas?" ‘mutant mige and showed that Toss of each of these tan- scription factors resulted in amelioration of many easical features of autoimmune disease, including bypergamma- slobulnaomis, ani-noclear autoantibodies and autontibod- ies aguins tse-speific antigens, Remarkably, only REL, Jan. 27, 2022

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