The Shionogi P2X3 ligand-gated ion channel antagonist, sivopixant ( S-600918 ), is an oral Ph. II candidate for refractory chronic cough, which recently completed a its Ph. IIb study, overcoming the projected high dose requirement of a prior preclinical candidate. The molecule has a very polar core structure with both a dioxotriazine and [...]

The Janssen PRMT5 inhibitor, onametostat (JNJ-64619178) is a selective, orally active and pseudo-irreversible protein arginine methyltransferase 5 (PRMT5) inhibitor with high selectivity and potency (subnanomolar range, PRMT5-MEP-50 IC50=0.14 nM) under various conditions. While JNJ-64619178 binds non-covalently in the PRMT5 SAM and [...]

The AstraZeneca PARP1-DNA trapper, AZD5305 , is a phase I candidate (NCT04644068) for cancer that is selective for PARP1 over PARP2 (>500x). Their study began by profiling the existing clinical and late-stage PARP inhibitors in vitro, finding that the seven leading compounds (olaparib, rucaparib, niraparib, talazoparib, veliparib, NMS-P118 [...]

The Sanofi S1P1 agonist, SAR247799 , is a biased agonist of the S1P1 sphingosine receptor, preferentially activating G-protein signaling over the β-arrestin and internalization pathways. Commercial S1P1 modulators such as fingolimod and ozanimod exert their immunosuppressive effects in multiple sclerosis and other diseases primarily by [...]

The ImmunoMet OXPHOS modulator (PC1 inhibitor), IM156 , is a derivative of the long-used biguanide diabetes drug, metformin, that appears to have activity in lung fibrosis models. The therapeutic hypothesis for IPF is that myofibroblasts play an essential role in extracellular matrix remodeling and fibrogenesis that lead to loss of pulmonary [...]

The BMS BET inhibitor, BMS-986158 , is in a Ph. I/IIa trial in advanced cancers. During the optimization of the molecule from a carbazole hit, the authors employed a bold scaffold-hopping strategy involving changing the direction of the carbazole core in order to better access a hydrophobic region of the target. The proposed new binding mode [...]

The Janssen BACE1-selective inhibitor, JNJ-67569762 , was a preclinical candidate for Alzheimer’s disease. Obtaining BACE1 over BACE2 selectivity was a major challenge in the field, and the molecule is 74x selective thanks to a bicyclic ring system in the S3 pocket. In in vivo models, BACE1-mediated PD was observed without BACE2-dependent [...]

The Entasis broad-spectrum antibiotic, ETX0462 , is both an inhibitor of penicillin-binding proteins (PBPs, the target of beta-lactams) and a beta-lactamase inhibitor (BLI). Reviewer Mike Koehler thought this was a substantial disclosure. “A number of BLIs co-formulated with carbapenems and monobactams are currently on the market. There are a [...]

The BMS factor XIa inhibitor, milvexian (BMS-986177), is an oral antithrombotic with a Ki of 0.11 nM. A member of this macrocyclic series was previously highlighted as one of 2020’s Molecules of the Year . Poor pharmaceutic properties from previous preclinical molecules such as solubility were addressed resulting in this candidate. Milvexian [...]

The GSK DNMT1 inhibitor GSK3685032 is a first-in-class, non-nucleoside, reversible and selective inhibitor of the epigenetic target DNA-methyltransferase 1 (DNMT1). Commonly prescribed hypomethylating agents (HMAs) such as decitabine are incorporated into DNA and inhibit DNMT1, DNMT3A, and DNMT3B irreversibly, and as a consequence are toxic [...]

The Deciphera CSF1R kinase inhibitor, vimseltinib (DCC-3014), is a selective oral TKI that induces an inactive conformation of CSF1R by biomimetically nucleating an array of 17 H-bonds in the switch control region of this switch control kinase. Several small and large molecule agents targeting CSF1R have been in development, and a small [...]

The Michigan bifunctional degrader, ARD-2585 , is similar to the Arvinas molecule, ARV-110 that was recently disclosed at AACR 2021. ARV-110 is a first-in-class, potent, and orally active AR degrader in clinical development, but understandably hasn’t had much published on it yet given the competitive environment. The publication of ARD-2585 [...]

The Bristol Myers Squibb (BMS)/Celgene GSPT1 degrader (CC-90009) is a CRBN-based molecular glue (CELMoD). It is a clinical candidate in Ph. I for AML and MDS, and in contrast to CC-92480 highlighted last March, spares the primary targets of prior imide drugs (IKZF1/3) and instead selectively degrades GSPT1 ( a target previously identified [...]

2. The Novartis LTA4H metalloenzyme inhibitor, LYS006, is a selective oral agent in multiple Ph. II studies to treat inflammatory diseases including ulcerative colitis and NASH. The starting points for this picomolar inhibitor were identified through a fragment based approach using differential scanning fluorimetry (DSF) as an initial binding [...]

3. The Eisai STING agonist E7766 leads to tumor eradication in 9/10 treated animals in a syngeneic model when injected intratumorally, and is currently in a Ph. I study for advanced solid tumors. The molecule has an interesting macrocyclic structure, and behaves as a cyclic dinucleotide mimic with potent activity on all four human STING variants.

4. The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations. The appearance of exon 20 insertions is a common resistance mechanism to earlier generations of EGFR inhibitors [...]

5. The Millenium/Takeda SUMO-activating enzyme (SAE) inhibitor TAK-981 is a mechanism-based inhibitor that covalently forms a SUMO substrate-inhibitor adduct that potently inhibits SAE, rather than reacting with SAE directly. The Takeda team has been able to successfully leverage this fascinating mechanism to develop potent inhibitors against [...]

The Bristol Myers Squibb (BMS) HPK1 kinase inhibitor, “compound 24” is an oral tool compound intended for cancer immunotherapy, with >50x selectivity against family members including GLK. The starting point was an IRAK4 kinase inhibitor identified from historical kinome selectivity data. A homology-model based on MST1 was used for [...]