1338806-73-7 Usage
Uses
(1R,?2S)?-2-?[3-?[(1E)?-?2-?[4-?[[(2R,?6S)?-?2,?6-?Dimethyl-?4-?morpholinyl]?methyl]?phenyl]?ethenyl]?-?1H-?indazol-?6-?yl]?-?5''-?methoxy-?spiro[cyclopropane-?1,?3''-?[3H]?indol]?-?2''(1''H)?-?one selectively inhibits polo-like kinase 4 (PLK4), which is a serine/threonine protein kinase that regulates centriole duplication during the cell cycle. PLK4 is a therapeutic target for various cancers.
Biological Activity
cfi-400945 is an orally active, potent and selective inhibitor of polo-like kinase 4.polo-like kinase 4 (plk4), a unique member of the polo-like family of kinases, shares little homology with other polo-like kinases. plk4 plays an essential role in centriole duplication. overexpression of plk4 overrides the centriole licensing mechanism and results in centriole amplification with multiple procentrioles forming around each parental centriole. depletion of plk4 by rnai prevents the formation of abnormal centrioles and microtubule-based structures, causing mitotic defects and in some cell lines it can induce apoptosis [2].in an assay using recombinant human plk4, cfi-400945 inhibited plk4 with an ic50 value of 2.8 ± 1.4 nm in an atp competitive manner with a ki value of 0.26 ± 0.1 nm. cfi-400945 inhibited autophosphorylation of plk4 at serine 305 with an ec50 value of 12.3 nm in cells overexpressing plk4 [1]. cfi-400945 showed no significant inhibitory activity against other plk family members (plk1, plk2, and plk3 with the ic50s of > 50 μm. in transfected hct116 cells with trka, trkb, and tie2/tek, the ec50 values were 84 nm, 88 nm, and 117 nm, respectively. cfi-400945 inhibited the activity of aurka and aurkb with the ec50 value of 510 nm and 102 nm. cfi-400945 (≥ 200 nm) decreased the mean centriole number in asynchronous u2os cells [1]. cfi-400945 inhibited a panel of breast cancer cell growth with the gi50 of 14-165 nm. in mice, the maximum tolerated dose (mtd) of cfi-400945 for once-daily oral administration was estimated to be 7.5-9.5 mg/kg [1].
references
[1] mason j m, lin d c c, wei x, et al. functional characterization of cfi-400945, a polo-like kinase 4 inhibitor, as a potential anticancer agent[j]. cancer cell, 2014, 26(2): 163-176.[2] sillibourne j e, bornens m. polo-like kinase 4: the odd one out of the family[j]. cell division, 2010, 5(1): 25.
Check Digit Verification of cas no
The CAS Registry Mumber 1338806-73-7 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,3,3,8,8,0 and 6 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1338806-73:
(9*1)+(8*3)+(7*3)+(6*8)+(5*8)+(4*0)+(3*6)+(2*7)+(1*3)=177
177 % 10 = 7
So 1338806-73-7 is a valid CAS Registry Number.
1338806-73-7Relevant articles and documents
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.
, 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.
