Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.

HiberCell recently disclosed the discovery of HC-7366, a potential first-in-class, intentionally discovered, orally bioavailable, potent, selective, small-molecule kinase activator of GCN2. HC-7366 has now progressed to Ph. I trials to treat ccRCC and AML. This case study is a fantastic example of how to mitigate CYP3A4 inhibition and improve oral bioavailability via judicious choice of salt formulation.

Sonrotoclax, BeiGene’s clinical-stage, orally bioavailable, next-generation inhibitor, targets both WT and mutated forms of the Bcl-2 protein by binding within a hydrophobic groove, similar to other inhibitors in its class. Explore this case study to see how sonrotoclax was rationally designed to potency against both WT and mutant Bcl-2 and address the limitations of first-generation inhibitors and more!

Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with >240M infections and >600K deaths each year, the majority of which are in sub-Saharan Africa. The need for new antimalarials is clear, given that over half of the world's population is at risk of infection, combined with the rise of resistance against current treatments. Novartis has played a key role in this fight and at the ACS Fall 2024 meeting in Denver, CO, they disclosed NVP-FVP954: a novel, fast-acting IV antimalarial for severe malaria.

Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.