Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells

Abstract

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer

“…Pan-RAF inhibitors can overcome this paradoxical activation by blocking WT A-, B-, and CRAF in addition to BRAF V600E. Although dimer formation is induced with pan-RAF inhibitors, MEK activation is abrogated because each dimer molecule is inhibitor-bound and lacks kinase activity (Henry et al 2015; Peng et al 2015). The pan-RAF inhibitor LY3009120 was found to be active in RAS -mutant cancer cell lines, including KRAS -mutant PDAC.…”

New perspectives for targeting RAF kinase in human cancer

“…LY3009120 is another αC-IN/DFG-OUT RAF inhibitor that showed antitumour activity in preclinical studies against NRAS or KRAS mutant tumours and vemurafenib-resistant melanomas 68,111 . LY3009120 binds to both RAF protomers within the BRAF dimer, stabilizing them in similar conformations, and, like other αC-IN RAF inhibitors, it inhibits monomeric and dimeric BRAF with similar potency 30,41,93 .…”

Targeting RAS -mutant Cancers: Is ERK the Key?

“…PLX8394 can also effectively block ERK activation and the growth of RAS -mutant vemurafenib-resistant melanoma cells [39] . Pan-RAF inhibitors - MLN2480, HM95573 and LY3009120- have also entered Phase I trials [40-42] . LY3009120 has shown in vitro and in vivo efficacy in inhibiting the ERK pathway without eliciting the effect of paradoxical activation [42] .…”

“…Pan-RAF inhibitors - MLN2480, HM95573 and LY3009120- have also entered Phase I trials [40-42] . LY3009120 has shown in vitro and in vivo efficacy in inhibiting the ERK pathway without eliciting the effect of paradoxical activation [42] . An alternative strategy for effective RAF inhibition in RAS -mutant cancers may be the use of small molecule inhibitors of RAF dimerization [43] .…”