1104467-40-4Relevant academic research and scientific papers
HPK1 INHIBITORS AND METHODS OF USING SAME
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Page/Page column 40, (2017/05/03)
Thienopyridinone compounds of Formula (I) and pharmaceutically acceptable salts thereof are described. In these compounds, one of X1; X2, and X3 is S and the other two are each independently CR, wherein R and all other variables are as defined herein. The compounds are shown to inhibit HPK1 kinase activity and to have in vivo antitumor activity. The compounds can be effectively combined with pharmaceutically acceptable carriers and also with other immunomodulatory approaches, such as checkpoint inhibition or inhibitors of tryptophan oxidation. Formula (I).
Discovery of 3-(5′-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation
Yan, Wei,Wang, Xinyi,Dai, Yang,Zhao, Bin,Yang, Xinying,Fan, Jun,Gao, Yinglei,Meng, Fanwang,Wang, Yuming,Luo, Cheng,Ai, Jing,Geng, Meiyu,Duan, Wenhu
supporting information, p. 6690 - 6708 (2016/08/06)
Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this article, we describe the identification of the potent pan-FGFR inhibitor (R)-21c (FGFR1-4 IC50 values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (R)-21c exhibited excellent in vitro inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analysis demonstrated that (R)-21c suppressed FGF/FGFR and downstream signaling pathways at nanomolar concentrations. Moreover, (R)-21c provided nearly complete inhibition of tumor growth (96.9% TGI) in NCI-H1581 (FGFR1-amplified) xenograft mice model at the dose of 10 mg/kg/qd via oral administration.
RADIOPROTECTOR COMPOUNDS AND METHODS
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Page/Page column 87, (2011/10/31)
The invention relates to novel compounds, processes for their preparation and their use in protecting biological materials from radiation damage (radioprotection). Preferred compounds of the invention are those of Formula (II), as follows: wherein W represents -N(R1R2) where R1 and R2 are not both hydrogen and where they may together form a 5, 6 or 7 membered ring structure, -NHN(R1R2), NHR3N(R1R2), -NHR3OR2, -N(R3)R3OR2, -N(R1)R3OR3OR3, OR3NR1R2, -OR3 or W represents piperidyl, piperazinyl, morpholinyl, thiomorpholinyl or diazepanyl each of which may be optionally substituted by C1 to C4 alkyl, C2 to C4 alkenyl, -N(CO)N(R1R2), -N(CO)OR1, -N(CO)OR3OH, -(CO)NR1R2, -R3(CO)NR1R2, -R3OR1, -OR1, -N(R1R2) OR -NH-; R1 and R2 are the or different and are selected from hydrogen, C1 to C4 alkyl or C2 to C4 alkenyl; group or chain; Z is the same or different and represents N or CH; Z' is the same or different and represents N or C; X represents CH, N or NH, where .. is a double bond when X is CH or N and a single bond when X is NH; X' represents N or NH, wherein when X is CH or N X' is NH and wherein X and X' are different and further where ～～～is a double bond when X' is N and a single bond when X' is NH; Q represents H, alkoxyl, -NR1R2, F or Cl; Q1 is absent when Z' is N and when Z' is C it represents H, alkoxyl, -NR1R2, F or Cl; A represents a five to ten membered single or multiple ring structure with heterocyclic N or O located at the ortho position, said ring including optional double bonds, substitutions and/or other heteroatoms and pharmaceutically acceptable derivatives thereof.
Design, structure-activity relationships and in vivo characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: Novel class of receptor tyrosine kinase inhibitors
Renhowe, Paul A.,Pecchi, Sabina,Shafer, Cynthia M.,Machajewski, Timothy D.,Jazan, Elisa M.,Taylor, Clarke,Antonios-McCrea, William,McBride, Christopher M.,Frazier, Kelly,Wiesmann, Marion,Lapointe, Gena R.,Feucht, Paul H.,Warne, Robert L.,Heise, Carla C.,Menezes, Daniel,Aardalen, Kimberly,Ye, Helen,He, Molly,Le, Vincent,Vora, Jayesh,Jansen, Johanna M.,Wernette-Hammond, Mary Ellen,Harris, Alex L.
experimental part, p. 278 - 292 (2009/10/17)
The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino- 3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP- competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC50 values 0.1 μM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
