January was an important month for Latigo Biotherapeutics who disclosed their preclinical small molecule Na_V1.8 inhibitor for non-opioid pain treatment that enters an increasingly competitive field led by Vertex’s VX-548. A potential first-in-class pan-PKC inhibitor currently in Ph. II/III trials for uveal melanoma and a macrocyclic peptide possessing a novel mechanism of action to treat carbapenem-resistant Acinetobacter baumannii infections also made the top ten list. Eli Lilly released details for their oral small molecule IL-17A inhibitor which was discontinued in a Ph. I clinical trial due to adverse events. Also featured this month are two small molecules currently in clinical trials from Cerevance/Takeda and Anavex for psychiatric conditions.

You can check out the recent articles about the January 2024 Molecules of the Month linked below:

1. LTGO-33 – A selective, state-independent, and potent preclinical small molecule Na_V1.8 inhibitor disclosed by Latigo Biotherapeutics that engages a novel interaction site and possesses a mechanism of action previously unreported for the treatment of pain disorders. 

2. darovasertib – A potent, oral, and potentially first-in-class pan-PKC inhibitor with high whole kinome selectivity and Orphan Drug designation discovered by Novartis, and being developed by Ideaya and Pfizer, is currently in Ph. II/III trials for primary and metastatic uveal melanoma. 

3. LY3509754 – Eli Lilly’s oral small molecule IL-17A inhibitor intended for psoriasis that was advanced to a Ph. I trial and ultimately discontinued due to adverse events consistent with drug-induced liver injury. 

4. CVN766 – An oral small molecule antagonist that is ~1000-fold selective for Ox1R over Ox2R reported by Cerevance and Takeda currently being evaluated in Ph. I trials for psychiatric conditions. 

5. MZ-101 – Maze Therapeutics’ oral and selective small molecule GYS1 inhibitor that decreased accumulation of glycogen in skeletal muscle in a mouse model of Pompe disease. 

6. zosurabalpin – A macrocyclic peptide bacterial LptB2FGC complex inhibitor reported by teams at Harvard and Roche currently in Ph. I clinical trials for carbapenem-resistant Acinetobacter baumannii infections.

7. afuresertib – An oral, ATP‐competitive pan-AKT small molecule inhibitor discovered by GSK, purchased by Novartis, and later Laekna, failed to significantly improve progression-free survival for ovarian cancer patients in a Ph. II trial. 

8. ANAVEX 3-71 – An oral, dual SIGMAR1 receptor agonist and M1 positive allosteric modulator with agonistic effects in development by Anavex that is being advanced to Ph. II trials for psychiatric conditions. 

9. exarafenib – Kinnate Biopharma’s highly potent pan-RAF kinase inhibitor that targets the α-C-helix-IN conformation, while sparing paradoxical MAPK signaling activation, currently in Ph. I trials for solid tumors. 

10. ORIC-101 – A potent, selective, and orally-bioavailable glucocorticoid receptor antagonist developed by ORIC Pharmaceuticals was well tolerated but did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide in a Ph. I trial.

Reviewer Commentary on CVN766 from Bryan McKibben

The authors describe the identification of an orexin-1 selective antagonist CVN766 for potential use in schizophrenia and related psychiatric conditions.  The starting point was an orexin-1 selective HTS hit with poor metabolic stability and MDR1 efflux pump challenges.  The authors were able to balance improvements in metabolic stability with reducing efflux by lowering LogD and shielding heteroatoms, respectively. This was all achieved while improving selectivity over orexin-2 receptor to >1000-fold… overall, an impressive example of multiparameter optimization.

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