Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.
Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada. Electronic address: swli@uhnresearch.ca.
Sze-Wan
SW
Li
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Yong
Y
Liu
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Peter B
PB
Sampson
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Narendra Kumar
NK
Patel
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Bryan T
BT
Forrest
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Louise
L
Edwards
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Radoslaw
R
Laufer
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Miklos
M
Feher
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Fuqiang
F
Ban
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Donald E
DE
Awrey
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Richard
R
Hodgson
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Irina
I
Beletskaya
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Guodong
G
Mao
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Jacqueline M
JM
Mason
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Xin
X
Wei
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Xunyi
X
Luo
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Reza
R
Kiarash
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Erin
E
Green
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Tak W
TW
Mak
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
Guohua
G
Pan
Campbell Family Institute for Breast Cancer Research, University Health Network, Princess Margaret Cancer Research Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada. Electronic address: henry.pauls@cogeco.ca.
Henry W
HW
Pauls
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D015195:Drug Design; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats
D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; C057812:indoline; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases
(1H-Indazol-6-yl)-methylene)indolin-2-ones; Antitumor agent; PLK4 inhibitors; Polo-like kinase 4; Spiro[cyclopropane-1,3′-indolin]-2′-ones