IAG933 is Novartis’ potential first-in-class small molecule inhibitor of the PPI between YAP/TAZ and TEAD, currently in a Ph. I trial for solid tumors with Hippo pathway alterations. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to inform hit selection and guide lead optimization, how to employ multiparameter optimization to circumvent cardiotoxicity liabilities, and how to redirect metabolism.

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.

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!

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.

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.