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Feb. 29, 2024

SOS1 and SMARCA2 Degraders, RORγ and IRAK4 Inhibitors, and More: January 2024 Compound Collection

Editor:  

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here, we have compiled a table of >70 additional molecules that were of interest in January 2024, along with highlights from some of our favorites below.

Jump to Searchable Table

A Potent and Selective Preclinical SOS1 Degrader that Shows Synergy with KRAS and MEK Inhibitors

BTX-6654 is a preclinical, cereblon-based bifunctional SOS1 degrader published by BioTheryX. Importantly, SOS1 degraders represent a potential modality for pan-KRAS inhibition that may be capable of circumventing acquired resistance mechanisms associated with allele-specific KRAS G12C inhibitors. BTX-6654 exhibited potent target-dependent and specific SOS1 degradation, reduced downstream signaling markers (pERK and pS6), and displayed antiproliferative activity in cells harboring various KRAS mutations. Notably, the discovery team found that BTX-6654 degraded SOS1 in a dose-dependent manner, correlating with tumor growth inhibition, and exhibited efficacy in combination with KRAS and MEK inhibitors. 

An Oral IRAK4 Inhibitor in Ph. II Trials for Atopic Dermatitis from Bayer AG

Bayer AG disclosed the discovery of BAY1834845 (zabedosertib), an oral IRAK4 inhibitor currently in Ph. II trials for atopic dermatitis. IRAK4 is ubiquitously expressed and plays a critical role in innate inflammatory processes. A number of IRAK4 inhibitors, alone or in combination with other agents, have advanced to clinical trials for the treatment of inflammatory diseases, including Kymera Therapeutics’ lead compound, KT-474. An initial hit compound was identified through an HTS screening campaign of Bayer’s in-house library of 3 million compounds. Then using a docking model, the team exploited the binding site features distinct to IRAK4 to remove the liabilities of the original hit compound. Subsequent SAR and PK optimization led to the identification of BAY1834845, which exhibited excellent biochemical potency, kinase selectivity, and oral PK profiles across preclinical species. Additionally, BAY1834845 showed significant anti-inflammatory in vivo efficacy in three relevant PD inflammation models, leading to its selection for clinical advancement

The Discovery of JTE-151: An Oral RORγ Inhibitor from Japan Tobacco that Appears Terminated After Ph. I

Japan Tobacco published the discovery of their oral RORγ inhibitor, JTE-151. RORγ was a hot target over the past decade for inflammatory and autoimmune diseases, with several small molecules reaching clinical development, but none of them have yet to reach the market. A potential reason for this lack of clinical success could be insufficient selectivity due to the general homology of nuclear receptor ligands, as well as poor physicochemical properties of the clinical compounds. Based on these hypotheses, the team prioritized SAR studies, starting from a series they had reported on previously to optimize drug-like properties. JTE-151 was ultimately identified, exhibiting a high selectivity profile over other nuclear receptors, good metabolic stability, good PK profile, and in vivo efficacy as demonstrated in a mouse EAE model. JTE-151 was subsequently advanced to Ph I. trials but appears to have been terminated as of May 2016.

A Preclinical SMARCA2 Degrader with In Vivo Efficacy and a Notable PK/PD Relationship

Genentech and Arvinas disclosed the discovery of compound 19, a preclinical PROTAC that potently degrades SMARCA2 in SW1573 cell-based assays. Compound 19 exhibits 28-fold degradation selectivity for SMARCA2 over the closely related paralog protein SMARCA4. In vivo experiments with a subset of PROTACs also showed potency and selective SMARCA2 degradation in the Calu6 and/or the HCC2302 SMARCA4 mutant NSCLC xenograft models with antitumor efficacy observed in the latter system. The team also established a notable PK/PD relationship that suggests >95% SMARCA2 degradation is needed to trigger meaningful antitumor activity in vivo.

A Preclinical NLRP3 inhibitor with a Unique Binding Mode from Novartis (Basel)

The discovery of NP3–562, an oral, preclinical NLRP3 inhibitor, was published by Novartis (Basel). The NLRP3 inflammasome has been implicated in a plethora of diseases, including type 2 diabetes, atherosclerosis, and cancer, among others. Through an HTS campaign, the team identified a structurally unique, tricyclic, NLRP3-binding scaffold. The hit compound was then optimized into NP3-562, exhibiting excellent human WB potency and full inhibition of IL-1β release in a mouse acute peritonitis model. Notably, X-ray structural analysis of NP3–562 bound to the NLRP3 NACHT domain (PDB: 8RI2) revealed a unique binding mode as compared to known sulfonylurea-based inhibitors. NP3-562 now joins the increasingly crowded NLRP3 inflammasome inhibitor space, led by NodThera’s CNS-penetrant prodrug, NT-0796, currently in Ph. Ib/IIa trials (NCT06129409).

You can browse or search through dozens of additional molecules and targets from January 2024 with recent disclosures or updates in the table below.

Drug NameMoACompany - OriginatorClinical Development CategoryTherapeutic Indication
AB-452PAPD5/7 inhibitorBaruch S. Blumberg Institute, Drexel University College of Medicinepreclinicalinfectious diseaseshepatitis B virus
AJ2-30SLC15A4 inhibitorThe Scripps Research Institutepreclinicalimmunologyautoimmune diseases
AR-15512TRPM8 agonistInstituto de Neurociencias de Alicantephase 3ophthalmologydry eye disease
BAY 60-2770sGC activatorBayer AGpreclinicalcardiologycoronary artery spasm
BAY1830839IRAK4 inhibitorBayer AGphase 1immunologyimmune mediated inflammatory diseases, arthritis, rheumatoid
BBO-8956SW2/α3 pocket KRAS G12C (ON) inhibitorLeidos Biomedical Researchpreclinicaloncologyoncology
BCH-HSP-C01ATG9A modulatorHarvard Medical SchoolpreclinicalneurologyND
bexicaserin5-HT2C receptor agonistLongboard Pharmaceuticalsphase 2neurologydevelopmental and epileptic encephalopathies
bezuclastinibKIT activation loop mutation exon 17/18 inhibitorPlexxikonphase 3oncologygastrointestinal stromal tumor
BNC210a7nAChR negative allosteric modulatorBionomics Limitedphase 2neurologypost-traumatic stress disorders, anxiety disorders, agitation
BRD1732broad ubiquitin-proteasome inhibitorUCSFpreclinicaloncologyoncology
BTX-6654SOS1 degraderBioTheryXpreclinicaloncologyoncology
CBI1BAX inhibitorDana-Farber Cancer InstitutepreclinicaloncologyND
compound 11cperipheral 5HT2A antagonistKorea Advanced Institute of Science and TechnologypreclinicalhepatologyMASH
compound 14TLR7 agonistBristol Myers Squibbpreclinicaloncologyoncology
compound 14cFXIa inhibitorPuchuang Pharmaceutical Technology (Tianjin)preclinicalhematology/cardiologyND
compound 15PHD InhibitorInsilico Medicine Shanghaipreclinicalhematologyanemia
compound 18PDE3B inhibitorGSKpreclinicalendocrinologymetabolic diseases
compound 19SMARCA2 degraderArvinas, Genentechpreclinicaloncologyoncology
compound 20TLR7 agonistBristol Myers Squibbpreclinicaloncologyoncology
compound 30fTRK inhibitorShanghai Institute of Pharmaceutical Industrypreclinicaloncologyoncology
compound 31Cbl-b inhibitorAstraZenecapreclinicaloncologyN/A
compound 46TSLP inhibitorAstraZenecapreclinicalimmunologyautoimmune diseases
compound 8PARP7 inhibitorWuhan Yuxiang Pharmaceutical Technology, Guizhou Universitypreclinicaloncologyoncology
compound 8CDO1 glue degraderNovartis Biomedical ResearchpreclinicaloncologyND
compounds 2jhPTHR1 agonistChugai PharmaceuticalpreclinicalendocrinologyND
compounds 3a and 3bnucleotide reverse transcriptase inhibitorJiangsu Tasly Diyi Pharmaceuticalpreclinicalinfectious diseaseshepatitis B
Cpd-1apo-TDO2 inhibitorIdorsia PharmaceuticalspreclinicaloncologyND
danicopancomplement factor D inhibitorAchillion PharmaceuticalsMHLW-Approved Japanhematologyparoxysmal nocturnal haemoglobinuria
DBt-10DCAF1-BTK PROTACNovartis Institutes for BioMedical ResearchpreclinicaloncologyND
deuremidevirRNA-dependent RNA polymerase inhibitorVigonvita Life Sciencesphase 3infectious diseasesCOVID-19
DHES0815AHER2-directed ADCGenentechphase 1oncologyHER2-positive breast cancer
dusquetidep62 modulatorUniversity of British Columbiaphase 3rheumatologyoral mucositis
eAmSPC-2593bacterial ribosome inhibitorSt. Jude Children’s Research Hospitalpreclinicalinfectious diseasesinfectious diseases
Ebio1KCNQ2 activatorEast China Normal University, Zhejiang University School of MedicinepreclinicalneurologyND
edaravoneFree radical scavenger (MoA has not been fully elucidated)Treewayphase 3neurologyamyotrophic lateral sclerosis, ischemic stroke
elinzanetantNK1 and NK3 receptor antagonistGlaxoSmithKlinephase 3gynecologyvasomotor symptoms associated with menopause
FPFT-2216CK1α and IKZF1/3 degraderFujimoto Pharmaceutical Corporationpreclinicaloncologyoncology
gartisertibATR inhibitorVertex Pharmaceuticalsphase 1/2oncologysolid tumors
GM-1020NMDA receptor antagonistGilgamesh Pharmaceuticalsphase 1psychiatrydepressive disorders
IbezapolstatDNA polymerase IIIC inhibitorsGLSynthesisphase 2infectious diseasesclostridium difficile infection
J-2156SST4 receptor agonistThe University of Queenslandpreclinicalendocrinologydiabetic neuropathy
janagliflozinSGLT2 inhibitorSihuan Pharmaceutical Holdings GroupNMPA-approved (China)endocrinologytype 2 diabetes
JRD-­ SIK1/2i-­ 4SIK1/2 inhibitorJanssen Research and Developmentpreclinicalimmunologyinflammatory diseases
JTE-151RORγ inhibitorJapan Tobaccophase 1rheumatology/immunologyautoimmune diseases
K2-B4-5e and K2-AR-1KLHDC2-based BET-family and AR protein PROTAC degradersArvinaspreclinicaloncologyND
KIN-3248irreversible pan-FGFR inhibitorKinnate Biopharmaphase 1oncologyadvanced tumors harboring FGFR2 and/​/​or FGFR3 gene alterations
laquinimodN/AActive Biotechphase 3neurologymultiple sclerosis
mazdutideGLP-1 receptor agonistEli Lilly and Companyphase 3endocrinologyobesity, type 2 diabetes
MG-002eIF4A RNA helicase inhibitorMcGill Universitypreclinicaloncologyoncology
MP-467 and MP-793Mdm2/X antagonistsGenentech, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, MSD Internationalpreclinicaloncologyoncology
NP3-562NLRP3 inhibitorNovartis Biomedical Researchpreclinicalimmunologyinflammatory diseases
obefazimodmiR-124 modulatorSplicosphase 3immunologyulcerative colitis
ompenaclidSLC6A8 inhibitorRgenixphase 2oncologycolorectal cancer
onvansertibPLK1 inhibitorNerviano Medical Sciencesphase 2oncologyoncology
PF-07957472SARS-CoV-2 PLpro inhibitorPfizerpreclinicalinfectious diseasesCOVID-19 infection
piclidenosonA3 adenosine receptor agonistCan-Fite BioPharmaphase 3rheumatologyplaque psoriasis, rheumatoid arthritis
PM534tubulin inhibitorPharmaMarphase 1oncologyadvanced solid tumors
pridopidineS1R agonistNeuroSearch Sweden ABphase 3neurologyamyotrophic lateral sclerosis, Huntington's disease
R-DXdCDH6-targeting, DNA topoisomerase I inhibitor ADCDaiichi Sankyophase 2/3oncologysolid cancer
RGH-122V1a receptor antagonistGedeon Richterpreclinicalneurologyautism
RMC-4998 and RMC-4550RASG12C(ON) inhibitor and SHP2 inhibitorRevolution Medicinespreclinicaloncologyoncology
RO7196472 and RO7075573bacterial LptB2FGC complex inhibitorRoche Pharma Research and Early Developmentpreclinicalinfectious diseasesbacterial infections
ropidoxuridineradiation-sensitising agentShuttle Pharmaceuticalsphase 2oncologyoncology
SCY-247glucan synthase inhibitorScynexispreclinicalinfectious diseasesinfectious diseases
SHR2554EZH2 inhibitorJiangsu Hengrui Medicinephase 3oncologyT-cell lymphoma
simnotrelvir3CLpro inhibitorShanghai Institute of Materia MedicaNMPA-approved (China)infectious diseasesCOVID-19
SJ3149CK1α degraderSt. Jude Children’s Research Hospitalpreclinicaloncologyoncology
SRI-41315eRF1 degraderUniversity of Alabama at Birminghampreclinicalgenetic diseasesND
TNX-102 SLserotonin2A receptor, α1-adrenergic receptor, histamine H1 receptor, muscarinic M1 receptor antagonistVela Pharmaceuticalsphase 3neurologyfibromyalgia
TP0628103MMP-7 inhibitorTaisho Pharmaceuticalpreclinicaloncologyoncology, fibrosis
TRP-88035HT2A receptor agonistTRYP Therapeuticsphase 1neurologyneurology
WD6305METTL3 and METTL14 complex degraderLingang Laboratory, Chinese Academy of Sciencespreclinicaloncologyoncology
WX-02-23SF3B1 inhibitorThe Rockefeller UniversitypreclinicalN/AND
YZJ-4729μ-opioid receptor agonistChina Pharmaceutical University, Nanjing Jiening Pharmaceutical Technologyphase 1pain managementpain management
zabedosertib (BAY1834845)IRAK4 inhibitorBayer AGphase 2dermatologyatopic dermatitis

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