CDI (Clostridioides difficile) infection is a leading cause of healthcare-associated diarrhea with significant morbidity and mortality, and with the rise of hypervirulent and resistant strains, novel and selective antibiotics to treat these infections are needed. Cadazolid, a hybrid antibiotic that combines pharmacophores of two classes of antibacterials, demonstrated potent activity in vitro against relevant C. difficile strains, while avoiding native gut flora. Additionally, the compound was designed to be gut-restricted, with minimal systemic circulation following PO dosing.

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.

EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. This is an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency.

BMS-986397 is a potential first-in-class CRBN-based selective CK1α molecular glue degrader. CK1α promotes tumor growth by enhancing MDM2 and MDMX degradation of the tumor suppressor p53. Since AML has a low TP53 mutation rate, activating the p53 pathway is a promising approach; however, p53 activators have faced challenges due to hematological toxicities. Targeting CK1α degradation offers an alternative approach. The BMS team sought to develop a CELMoD® for CK1α degradation. This article outlines the discovery of BMS-986397, as presented at the ACS Fall 2024 meeting in Denver, CO.

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.