NDI-101150 is an oral HPK1 inhibitor discovered by Nimbus Therapeutics and is currently in Ph. I/II clinical trial in advanced solid tumors. HPK1 is a compelling immuno-oncology target due to its critical role in regulating T-cells, B-cells, and dendritic cell-mediated immune responses. HPK1-deficient mice demonstrate enhanced anti-tumor T-cell responses and resistance to tumor growth. In this article, we detail the discovery of NDI-101150, as highlighted by Nimbus at the ACS Fall 2024 First-Time Disclosures session, interim results from the clinic, and more.

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant PI3Kα (phosphatidylinositol-3 kinase α) targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.

AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.

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.

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.