Reference Detail

Ref Type

Journal Article

PMID

(22319199)

Authors

James J, Ruggeri B, Armstrong RC, Rowbottom MW, Jones-Bolin S, Gunawardane RN, Dobrzanski P, Gardner MF, Zhao H, Cramer MD, Hunter K, Nepomuceno RR, Cheng M, Gitnick D, Yazdanian M, Insko DE, Ator MA, Apuy JL, Faraoni R, Dorsey BD, Williams M, Bhagwat SS, Holladay MW

Title

CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	11	4	2012 Apr	930-41	Mol Cancer Ther

URL

Abstract Text

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF(V600E) (K(d) BRAF(V600E) = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC(50) = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAF(V600E) versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10-55 mg/kg) of both pMEK and pERK in BRAF(V600E) colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30-100 mg/kg twice daily) against BRAF(V600E) melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RXDX-105	RXDX-105	7	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RXDX-105		AC013773\|CEP-32496\|Agerafenib	ABL Inhibitor (pan) 9 ABL1 Inhibitor 8 BCR-ABL Inhibitor 31 BRAF Inhibitor 25 CRAF Inhibitor 12 KIT Inhibitor 57 PDGFR-beta Inhibitor 14 RET Inhibitor 52 VEGFR2 Inhibitor 37	Agerafenib (RXDX-105) inhibits wild-type BRAF, BRAF V600E, c-RAF, ABL1 (and BCR-ABL), c-KIT, RET, PDGFR beta, and VEGFR2, potentially resulting in decreased tumor growth (PMID: 22319199, PMID: 31695841).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	RXDX-105	Preclinical - Cell line xenograft	Actionable	In preclinical studies, CEP-32496 (RXDX-105) reduced tumor volume and promoted tumor regression in xenograft models of a BRAF V600E mutant human melanoma cell line (PMID: 22319199).	22319199
BRAF V600E	colon carcinoma	sensitive	RXDX-105	Preclinical - Cell line xenograft	Actionable	In preclinical studies, CEP-32496 (RXDX-105) reduced tumor volume and promoted tumor regression in xenograft models of a BRAF V600E mutant human colon carcinoma cell line (PMID: 22319199).	22319199