The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.
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The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3.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.
Peter B
PB
Sampson
Yong
Y
Liu
Bryan
B
Forrest
Graham
G
Cumming
Sze-Wan
SW
Li
Narendra Kumar
NK
Patel
Louise
L
Edwards
Radoslaw
R
Laufer
Miklos
M
Feher
Fuqiang
F
Ban
Donald E
DE
Awrey
Guodong
G
Mao
Olga
O
Plotnikova
Richard
R
Hodgson
Irina
I
Beletskaya
Jacqueline M
JM
Mason
Xunyi
X
Luo
Vincent
V
Nadeem
Xin
X
Wei
Reza
R
Kiarash
Brian
B
Madeira
Ping
P
Huang
Tak W
TW
Mak
Guohua
G
Pan
Henry W
HW
Pauls
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D061986:MCF-7 Cells; D008297:Male; D008819:Mice, Nude; D016513:Mice, SCID; D008956:Models, Chemical; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
C000592365:2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one; D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C456900:indolin-2-one; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases