LTGO-33 is a state-independent NaV1.8 inhibitor with over 600-fold selectivity for the NaV1.8 channel over other sodium channels. Chronic pain affects millions, and existing treatments offer limited efficacy, risk of abuse, and low tolerability. There is an urgent need for new drugs that target validated pain mechanisms such as NaV1.8, which has recently gained increased attention. This article explores the unique pharmacological properties of LTGO-33, setting it apart from earlier NaV1.8 inhibitors.

RMC-9805 is a first-in-class, covalent KRAS(G12D)(ON) molecular glue inhibitor from Revolution Medicines that uses a cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit the previously “undruggable” KRAS(G12D) mutant. Read our coverage of the discovery story, disclosed at the AACR 2024 meeting in San Diego, to discover how structural and modeling insights were key to engaging a poorly nucleophilic mutant Asp, how RMC-9805 synergizes with PD-1 inhibitors, and the progress this remarkable compound is making in the clinic.

Pfizer’s ritlecitinib, a first-in-class, selective, oral covalent inhibitor of JAK3 and the TEC family of kinases, was FDA-approved in June 2023 for the treatment of severe alopecia areata. Ritlecitinib derives its JAK-family kinase selectivity from the covalent modification of a unique cysteine on JAK3. This annotation reviews the discovery of ritlecitinib, highlighting the interpretation of selectivity assays, the PK optimization, the evolution of the JAK3 therapeutic hypothesis, and how this 2023 Molecule of the Year nominee has become a classic case study for covalent drug discovery.

Pfizer’s oral, CDK4-selective inhibitor PF-07220060 has the potential to revolutionize treatment of HR+/HER2- breast cancer through avoiding the neutropenia DLTs associated with SoC CDK4/6 drugs and permitting greater coverage of the desired CDK4 target. Our full article outlines data presented at AACR 2024, covering the molecule’s course from in silico-informed screen, through structurally enabled optimization against CDK6 and GSK-3β to promising preclinical profile. Fresh clinical data showed efficacy and tolerability supporting PF-07220060's clinical progression.

Atrasentan, an ETA receptor antagonist discovered by Abbott (AbbVie) in the 1990s, was initially developed for prostate cancer. Due to insufficient clinical data for approval, AbbVie shifted its focus to chronic kidney diseases, conducting a large trial (SONAR) with over 5,000 patients. AbbVie later exited kidney disease drug development and out-licensed atrasentan to Chinook. Novartis then surprised everyone with a $3.2B buyout of Chinook. This case exemplifies the complexities of drug discovery for kidney diseases and the long journey from initial research to clinical success.