AM-2-19 (SF001) is an analog of the notoriously toxic IV antifungal drug, amphotericin B (AmB). Compared with AmB, AM-2-19 is significantly less toxic against primary human cells and in mice, while more broadly active against fungal pathogens including antifungal drug-resistant strains. SF001 received Fast-Track Designation from the FDA in 2023 and has progressed to Ph. I clinical development. This article highlights the history of antifungal polyene natural products, a new mechanistic hypothesis for polyene antibiotic activity, and the design of 3rd generation Erg-specific polyenes.

The recently released WHO INN proposed names list includes the structure and name of Structure Therapeutics’ oral small molecule GLP-1R agonist, aleniglipron (GSBR-1290). Seemingly emerging from a “fast-follower” program based on Chugai/Eli Lilly’s orforglipron, the compound includes an unusual phosphine oxide motif and has shown positive results on plasma glucose levels and bodyweight in a Ph. IIa study.

Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

PLX-4545 is an oral CRBN-based molecular glue degrader of IKZF2 in Ph. I trials. It potentially addresses anti-tumor immunity suppression within the TME, critical in checkpoint blocker resistance. Tumors use IKZF2 to regulate the function of regulatory T cells and inhibit effector T cells. IKZF2 depletion in regulatory T cells enhances the anti-tumor response. The discovery and structural data of PLX-4545 were presented by Kevin Freeman-Cook at the ACS Fall 2024 First-Time Disclosures session in Denver, CO. We are reporting the discovery story and its potential impact on immuno-oncology.

This month’s cover molecule, Pfizer’s PF-07321332 (nirmatrelvir, API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which has been submitted to the FDA by Pfizer for emergency approval for Covid treatment. Interim data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for this month’s [...]