Journal of medicinal chemistry · 2024
Identification of the Clinical Candidate PF-07284890 (ARRY-461), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Ren Li, Moreno David, Baer Brian R, Barbour Patrick, Bettendorf Tanna, Bouhana Karyn, Brown Karin, Brown Suzy A, Fell Jay B, Hartley Dylan P, Hicken Erik J, Laird Ellen R, Lee Patrice, McCown Joseph, Otten Jennifer N, Prigaro Brett, Wallace Ross, Kahn Dean
Аннотация
Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).