title: Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.
abstract: Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Kevin K-C
authors.initials: KK
authors.lastname: Liu
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: JinJiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Qinhua
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Qing J
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Marx
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Paderes
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Richardson
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Marlena
authors.initials: M
authors.lastname: Walls
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wells
authors.forename: Sangita
authors.initials: S
authors.lastname: Baxi
authors.affiliation: Chemistry Department, Oncology, Pfizer Global Research and Development , 10770 Science Center Drive, La Jolla, California 92120, United States.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zou
keywords: Kinase inhibitor; PI3K; antitumor activity; mTOR; thiophene; triazole