660823-36-9Relevant articles and documents
From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor
Turner, Lewis D.,Trinh, Chi H.,Hubball, Ryan A.,Orritt, Kyle M.,Lin, Chi-Chuan,Burns, Julie E.,Knowles, Margaret A.,Fishwick, Colin W. G.
, p. 1481 - 1504 (2021/12/02)
Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.
Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities
Zhang, Mingliang,Fang, Xiaobao,Wang, Cong,Hua, Yi,Huang, Chen,Wang, Meng,Zhu, Lu,Wang, Zixu,Gao, Yuhan,Zhang, Tianyi,Liu, Haichun,Zhang, Yanmin,Lu, Shuai,Lu, Tao,Chen, Yadong,Li, Hongmei
, (2020/08/26)
Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selec
Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor
Bommi-Reddy, Archana,Brucelle, Francois,Cantone, Nico,Cummings, Richard T.,Gardberg, Anna S.,Huhn, Annissa,Levell, Julian R.,Patel, Chirag,Patel, Gaurav,Poy, Florence,Sims, Robert J.,Wilson, Jonathan E.
supporting information, p. 1324 - 1329 (2020/07/03)
The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.
