1247001-30-4Relevant articles and documents
Selective and efficient synthesis of trans-arylvinylboronates and trans-hetarylvinylboronates using palladium catalyzed cross-coupling
Liu, Zhihao,Wei, Wei,Xiong, Lu,Feng, Qiang,Shi, Yaojie,Wang, Ningyu,Yu, Luoting
supporting information, p. 3172 - 3176 (2017/04/14)
trans-Arylvinylboronate derivatives are important synthesis blocks in natural products, pharmaceuticals and organic materials. There are only a few reaction conditions that could selectively provide trans-arylvinylboronates by Heck coupling of pinacol vin
The discovery of polo-like kinase 4 inhibitors: Design and optimization of spiro[cyclopropane-1,3′[3H]indol]-2′(1′H).ones as orally bioavailable antitumor agents
Sampson, Peter B.,Liu, Yong,Patel, Narendra Kumar,Feher, Miklos,Forrest, Bryan,Li, Sze-Wan,Edwards, Louise,Laufer, Radoslaw,Lang, Yunhui,Ban, Fuqiang,Awrey, Donald E.,Mao, Guodong,Plotnikova, Olga,Leung, Genie,Hodgson, Richard,Mason, Jacqueline,Wei, Xin,Kiarash, Reza,Green, Erin,Qiu, Wei,Chirgadze, Nickolay Y.,Mak, Tak W.,Pan, Guohua,Pauls, Henry W.
, p. 130 - 146 (2016/09/09)
Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved physicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.
The discovery of polo-like kinase 4 inhibitors: Identification of (1 R,2 S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1 H -indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent
Sampson, Peter B.,Liu, Yong,Forrest, Bryan,Cumming, Graham,Li, Sze-Wan,Patel, Narendra Kumar,Edwards, Louise,Laufer, Radoslaw,Feher, Miklos,Ban, Fuqiang,Awrey, Donald E.,Mao, Guodong,Plotnikova, Olga,Hodgson, Richard,Beletskaya, Irina,Mason, Jacqueline M.,Luo, Xunyi,Nadeem, Vincent,Wei, Xin,Kiarash, Reza,Madeira, Brian,Huang, Ping,Mak, Tak W.,Pan, Guohua,Pauls, Henry W.
supporting information, p. 147 - 169 (2015/03/03)
Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.
KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
-
, (2011/10/31)
The invention is directed to a compound represented by the following structural formula pharmaceutically acceptable salts thereof: (I). Compounds represented by this structural formula are kinase inhibitors and are therefore disclosed herein for the treatment of cancer. Definitions for the variables in the structural formula are provided herein.
