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.

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.

BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Amyloid deposits in the heart muscle characterize the rare but potentially fatal disease. This case study reviews the history of TTR modulation, early experiments validating the therapeutic potential of TTR stabilization, the binding mechanism of acoramidis to TTR, the importance of binding enthalpy for differentiation, and the molecule’s impressive 30-month clinical data following an early scare.

AbbVie’s ABBV-467 is a highly potent, selective MCL-1 (myeloid cell leukemia-1) inhibitor which entered the clinic in 2022 in a Ph. I trial in patients with advanced hematologic cancers. MCL-1 has had a rough time in the clinic with multiple trials being halted or terminated due to cardiac toxicity, which is suspected to be an on-target effect. AbbVie’s approach with ABBV-467 was to target a highly potent/short half-life compound which could induce rapid apoptosis and tumor regressions in a short exposure period before the onset of any adverse events. Is this the end for MCL-1?

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.