A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Oncogenic BRAF mutations, particularly (V600E)BRAF, are key drivers of cancer cell proliferation and survival.
• Targeting mutant BRAF is a validated therapeutic strategy in oncology.
• There is a need for selective inhibitors of mutant BRAF with favorable pharmacokinetic properties.

Purpose of the Study:

• To develop and characterize a novel, potent inhibitor of (V600E)BRAF, designated 1t (CCT239065).
• To evaluate the selectivity, efficacy, and pharmacokinetic profile of 1t in preclinical cancer models.

Main Methods:

• In vitro biochemical and cellular assays to assess BRAF inhibition and downstream signaling.
• In vivo studies using human tumor xenografts with wild-type and mutant BRAF.
• Pharmacokinetic studies in mice to determine oral bioavailability.

Main Results:

• 1t potently inhibits (V600E)BRAF, blocking DNA synthesis and proliferation in cancer cells.
• 1t demonstrates significant selectivity for mutant BRAF cancer cell lines over wild-type BRAF lines.
• 1t exhibits excellent oral bioavailability (71%) and is well tolerated in mice.
• Oral administration of 1t suppressed (V600E)BRAF signaling in xenografts and elicited significant therapeutic responses in mutant BRAF melanoma models, while sparing wild-type BRAF tumors.

Conclusions:

• 1t is a potent and selective inhibitor of (V600E)BRAF with promising preclinical efficacy.
• The favorable pharmacokinetic profile and demonstrated therapeutic activity support further development of 1t as a targeted cancer therapy.