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STX-478: A Next-Generation Mutant-Selective PI3Kα Allosteric Inhibitor with a Potentially Improved Safety Profile STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα), 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…

LUNA18: A Clinical, Oral, Cell-Penetrant, Reversible, Macrocyclic Peptide Pan-RAS Inhibitor from mRNA Display LUNA18 is an orally bioavailable, cell-penetrant, macrocyclic peptide pan-RAS inhibitor (Chugai ’21Q3 earnings call) intended for the treatment of KRAS-mutant cancers. It disrupts the protein-protein interaction between KRAS and SOS, preventing RAS activation. The molecule is an important proof-of-concept for macrocycles, as…

FLX475: An Azetidine-Containing, First-in-Class CCR4 Candidate with a 72 h Human Half-life RAPT Therapeutics, formerly known as FLX Bio, was spun out of Flexus Biosciences after its billion-dollar acquisition by BMS for Flexus’s immuno-oncology IDO1 program. While the IDO1 molecule unfortunately did not show efficacy in Ph. III trials in combination with BMS’s PD-1 inhibitor…

A DCAF1 Ligand Designed for Targeted Protein Degradation Targeted protein degraders continue to show differentiation from traditional small molecules in terms of both efficacy and safety. To expand the scope of targeted protein degradation (TPD), there has been significant interest throughout the industry in leveraging new E3 ligases beyond CRBN, VHL, MDM2, cIAP, and SCF.…

The First Isoform-Selective FGFR2 Inhibitor The FGFR family of receptors are well-validated targets in cancer, and several pan-FGFR inhibitors that have strong activity against FGFR1-4 have reached approval including pemigatinib, infigratinib, futibatinib, and erdafitinib. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities, such as…

A Novel Class of Brain-Penetrant, Covalent Antiparasitic Drugs from Novartis Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetoplastid parasites cause Chagas disease (T. cruzi), sleeping sickness (T. brucei), and leishmaniasis (Leishmania), but there are few effective treatment options, especially for infections in the brain (e.g. stage II…