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

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.

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.