Plexxikon today announced publication of key data in this week's edition of Nature demonstrating that the high degree of selectivity of PLX4032 (RG7204) enables substantial RAF/MEK/ERK pathway inhibition, which may be necessary to achieve significant tumor shrinkage and clinical response in patients with BRAF mutant melanoma. The paper details the structure-guided discovery of PLX4032, a novel, investigational, targeted agent, selective for the oncogenic BRAF mutation prevalent in melanoma and other cancers. The findings support recently published data from the New England Journal of Medicine showing that nearly all mutation-positive patients in a Phase 1 clinical trial of PLX4032 experienced some tumor shrinkage.
“These data provide important support for our clinical development of PLX4032, and are a direct translation of our preclinical data demonstrating that comprehensive inhibition of the ERK pathway may be necessary for significant tumor regression”
Following the initial identification of mutant BRAF in melanomas and other cancers in 2002, Plexxikon leveraged its structure-guided discovery approach to identify and optimize a number of inhibitors selective for mutant BRAF, including PLX4032.
Preclinical studies showed that PLX4032 selectively blocks the RAF/MEK/ERK pathway in BRAF mutant cells and causes regression of tumors in BRAF mutant xenograft models. Toxicology studies confirmed a high therapeutic index consistent with a high degree of selectivity.
Tumor regression in cancer patients requires significant pathway inhibition