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Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors.

Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy E, Johannes J, Lee S, Lyne P, Mörtl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M
J Med Chem 56 1996-2015 (2013)
Cited: 16 times
EuropePMC logo PMID: 23398453

Abstract

B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.

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  1. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Ruiz-Castillo P, Buchwald SL. Chem. Rev. 116 12564-12649 (2016)
  2. Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: synthetic approaches and multifarious applications. Khan I, Ibrar A, Abbas N, Saeed A. Eur J Med Chem 76 193-244 (2014)
  3. Approaches toward improving the prognosis of pediatric patients with glioma: pursuing mutant drug targets with emerging small molecules. Snape TJ, Warr T. Semin Pediatr Neurol 22 28-34 (2015)
  4. Applications of palladium-catalyzed C-N cross-coupling reactions in pharmaceutical compounds. Emadi R, Bahrami Nekoo A, Molaverdi F, Khorsandi Z, Sheibani R, Sadeghi-Aliabadi H. RSC Adv 13 18715-18733 (2023)

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  1. Molecular dynamics simulations and modelling of the residue interaction networks in the BRAF kinase complexes with small molecule inhibitors: probing the allosteric effects of ligand-induced kinase dimerization and paradoxical activation. Verkhivker GM. Mol Biosyst 12 3146-3165 (2016)
  2. Deep phylogeny of cancer drivers and compensatory mutations. Rochman ND, Wolf YI, Koonin EV. Commun Biol 3 551 (2020)
  3. The chemistry and pharmacology of privileged pyrroloquinazolines. Chao B, Li BX, Xiao X. Medchemcomm 6 510-520 (2015)
  4. Optimization of diarylthiazole B-raf inhibitors: identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect. Pulici M, Traquandi G, Marchionni C, Modugno M, Lupi R, Amboldi N, Casale E, Colombo N, Corti L, Fasolini M, Gasparri F, Pastori W, Scolaro A, Donati D, Felder E, Galvani A, Isacchi A, Pesenti E, Ciomei M. ChemMedChem 10 276-295 (2015)
  5. AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status. Ma R, Xu L, Qu X, Che X, Zhang Y, Fan Y, Li C, Guo T, Hou K, Hu X, Drew L, Shen M, Cheung T, Liu Y. Br. J. Cancer 118 1453-1463 (2018)
  6. Difference contact maps: From what to why in the analysis of the conformational flexibility of proteins. Iyer M, Li Z, Jaroszewski L, Sedova M, Godzik A. PLoS One 15 e0226702 (2020)
  7. Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- substituted triazine as PI3K and BRAF dual inhibitor. Wang HY, Shen Y, Zhang H, Hei YY, Zhao HY, Xin M, Lu SM, Zhang SQ. Future Med Chem 10 2445-2455 (2018)
  8. Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-RafV600E inhibitors. Hu CQ, Li K, Yao TT, Hu YZ, Ying HZ, Dong XW. Medchemcomm 8 1835-1844 (2017)


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