1. Identification of the Clinical Candidate PF-07284890 ( ARRY-461 ), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.
- Author
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Ren L, Moreno D, Baer BR, Barbour P, Bettendorf T, Bouhana K, Brown K, Brown SA, Fell JB, Hartley DP, Hicken EJ, Laird ER, Lee P, McCown J, Otten JN, Prigaro B, Wallace R, and Kahn D
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Female, Blood-Brain Barrier metabolism, Brain metabolism, Melanoma drug therapy, Melanoma pathology, Structure-Activity Relationship, Rats, Mice, Nude, Xenograft Model Antitumor Assays, Male, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use
- Abstract
Mutant BRAF
V600E 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).- Published
- 2024
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