Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

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.

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.

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.