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Ref Type Abstract
PMID
Authors Shuichan Xu; Tam Tran; Dan Zhu; Tao Shi; David Mikolon; Jim Leisten; Philip Chamberlain; Laurie LeBrun; Sogole Bahmanyar; Ning Jiang; Jingjing Zhao; Mehnaz Malek; Ellen Filvaroff; Heather Raymon; Robert Hubbard; John Boylan
Title Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 82 12_Supplement June 15, 2022
URL https://aacrjournals.org/cancerres/article/82/12_Supplement/1180/701075/Abstract-1180-Discovery-of-CC-91516-a-potent-and
Abstract Text CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223. Broad kinase selectivity profiling identified ERK1/2 and NLK as targets of CC-91516. Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994. This unique binding mode of CC-91516 leads to a slow off-rate for its ERK binding with long residence time disrupting both the active and inactive ERK forms. Consequentially, CC-91516 causes sustained inhibition of the MAPK pathway in BRAF mutant colorectal cancer cells. In addition, CC-91516 also regulates Wnt/β-catenin and YAP pathways in multiple cancer cell lines. CC-91516 shows potent yet selective anti-proliferative activity against a large panel of cancer cell lines. Activating mutations in BRAF or CTNNB1 gene associate with sensitivity to CC-91516-mediated anti-proliferative activity while mutations in RB and PI3K/PTEN pathway associate with resistance. CC-91516 inhibits ex vivo colony formation of PDX models with BRAF and CTNNB1 mutations. In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro. CC-91516 has good oral bioavailability and shows excellent anti-tumor activity in vivo against both BRAF and CTNNB1 mutant xenograft models. DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development.

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