Lois Commodore

TL;DR: Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.

TL;DR: Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells, and coupled with a favorable ADME profile, support the potential of 20G to be an effective treatment for CML, including patients refractory to all currently approved therapies.

TL;DR: The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues, and the extensive network of optimized molecular contacts found in the DFG‐out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations.

TL;DR: Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDh-A, suggesting target-specific inhibition in cancer cell lines.

TL;DR: Structural guidance is provided for the further design of novel potent DFG‐out class inhibitors against Src, Abl and Abl T315I mutant kinases.