Adhirai Marimuthu

TL;DR: The structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity, and a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily are described, demonstrating that BRAF-mutant melanomas are highly dependent on B- RAF kinases activity.

TL;DR: PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays and represents the entire discovery process from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B- RafV 600E-driven tumors.

TL;DR: Treating tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients, and the most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema.

TL;DR: PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy, and additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

TL;DR: Next-generation RAF inhibitors are identified (dubbed ‘paradox breakers’) that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation, a concept currently undergoing human clinical evaluation with PLX8394.