title: Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
abstract: Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Angove
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brain
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christine Hiu-Tung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Kristy
authors.initials: K
authors.lastname: Chung
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Claudio
authors.initials: C
authors.lastname: Dagostin
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Davis
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Feltell
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Giraldes
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hiscock
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Kovats
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Bharat
authors.initials: B
authors.lastname: Lagu
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewry
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Luzzio
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Wiesia
authors.initials: W
authors.lastname: Maniara
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mortenson
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Rajdeep
authors.initials: R
authors.lastname: Benning
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: O'Reilly
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Junqing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Troy
authors.initials: T
authors.lastname: Smith
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Williams
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wrona
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Astex Pharmaceuticals Inc. , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Howard
keywords: CDK4/6; fragment-based screening; mantle cell lymphoma; pRb phosphorylation; structure-guided optimization