894783-71-2Relevant articles and documents
Harnessing affinity-based protein profiling to reveal a novel target of nintedanib
Chen, Xiong,Li, Manru,Li, Menglin,Wang, Dongmei,Zhang, Jinlan
, p. 3139 - 3142 (2021/04/02)
Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.
Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth
Edupuganti, Ramakrishna,Taliaferro, Juliana M.,Wang, Qiantao,Xie, Xuemei,Cho, Eun Jeong,Vidhu, Fnu,Ren, Pengyu,Anslyn, Eric V.,Bartholomeusz, Chandra,Dalby, Kevin N.
, p. 2609 - 2616 (2017/04/06)
Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.
