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LUNA18

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

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…

PF-07054894

A squaramide-containing, insurmountable CCR6 antagonist for ulcerative colitis. PF-07054894 is a potential first-in-class, oral Ph. I clinical candidate targeting the chemokine receptor CCR6 for ulcerative colitis (NCT05549323). Several companies have pursued antibodies and small molecules targeting CCR6 or its endogenous ligand, CCL20 (e.g. GSK3050002) for immunological conditions including other preclinical squaramides (e.g. Galderma, Allergan, ChemoCentryx)…

AZD4747

A CNS-Penetrant KRASG12C Inhibitor Intended for CNS-Metastatic Cancers AZD4747 is a CNS-penetrant, oral KRASG12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability (MW < 360 Da, cLogD < 2, TPSA < 90 Å2).…

compound 13

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.…

lirafugratinib (RLY-4008)

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…