3C4E

Pim-1 Kinase Domain in Complex with 3-aminophenyl-7-azaindole

Summary for 3C4E

• Entry DOI: 10.2210/pdb3c4e/pdb
• Related: 3C4C 3C4D 3C4F
• Descriptor: Proto-oncogene serine/threonine-protein kinase Pim-1, IMIDAZOLE, N-phenyl-1H-pyrrolo[2,3-b]pyridin-3-amine, ... (4 entities in total)
• Functional Keywords: pim-1, proto-oncogene, serine/threonine kinase, alternative initiation, atp-binding, cytoplasm, manganese, membrane, metal-binding, nucleotide-binding, nucleus, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 4
• Total formula weight: 127184.51

Authors

Zhang, K.Y.J.,Wang, W. (deposition date: 2008-01-29, release date: 2008-02-26, Last modification date: 2024-02-21)

Primary citation

Tsai, J.,Lee, J.T.,Wang, W.,Zhang, J.,Cho, H.,Mamo, S.,Bremer, R.,Gillette, S.,Kong, J.,Haass, N.K.,Sproesser, K.,Li, L.,Smalley, K.S.,Fong, D.,Zhu, Y.L.,Marimuthu, A.,Nguyen, H.,Lam, B.,Liu, J.,Cheung, I.,Rice, J.,Suzuki, Y.,Luu, C.,Settachatgul, C.,Shellooe, R.,Cantwell, J.,Kim, S.H.,Schlessinger, J.,Zhang, K.Y.,West, B.L.,Powell, B.,Habets, G.,Zhang, C.,Ibrahim, P.N.,Hirth, P.,Artis, D.R.,Herlyn, M.,Bollag, G.
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Proc.Natl.Acad.Sci.Usa, 105:3041-3046, 2008

PubMed Abstract: BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.

PubMed: 18287029
DOI: 10.1073/pnas.0711741105

Experimental method

X-RAY DIFFRACTION (1.98 Å)