Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

被引：37

作者：

Lin, Songwen ^{[1
,2
,3
]}

Wang, Chunyang ^{[1
,2
]}

Ji, Ming ^{[1
,2
]}

Wu, Deyu ^{[1
,2
,3
]}

Lv, Yuanhao ^{[1
,2
]}

Zhang, Kehui ^{[1
,2
,3
]}

Dong, Yi ^{[1
,2
,3
]}

Jin, Jing ^{[1
,2
]}

Chen, Jiajing ^{[1
,2
,3
]}

Zhang, Jingbo ^{[1
,2
,3
]}

Sheng, Li ^{[2
,4
]}

Li, Yan ^{[2
,4
]}

Chen, Xiaoguang ^{[1
,2
]}

Xu, Heng ^{[1
,2
,3
]}

机构：

[1] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[2] Peking Union Med Coll, Beijing 100050, Peoples R China

[3] Chinese Acad Med Sci, Inst Mat Med, Beijing Key Lab Act Subst Discovery & Druggabil E, Beijing 100050, Peoples R China

[4] Chinese Acad Med Sci, Beijing Key Lab Nonclin Drug Metab & PK PD Study, Beijing 100050, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 14期

基金：

国家重点研发计划;

关键词：

BRAIN-PENETRANT; CLASS-I; CLINICAL DEVELOPMENT; PATHWAY ALTERATIONS; PI3K; IDENTIFICATION; GROWTH; CANDIDATE;

D O I：

10.1021/acs.jmedchem.8b00416

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

引用

页码：6087 / 6109

页数：23

共 38 条

[1] 3-phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase [J].

Alessi, DR ;

Deak, M ;

Casamayor, A ;

Caudwell, FB ;

Morrice, N ;

Norman, DG ;

Gaffney, P ;

Reese, CB ;

MacDougall, CN ;

Harbison, D ;

Ashworth, A ;

Bownes, M .

CURRENT BIOLOGY, 1997, 7 (10) :776-789

[2] New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays [J].

Baell, Jonathan B. ;

Holloway, Georgina A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) :2719-2740

[3] Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial [J].

Baselga, Jose ;

Im, Seock-Ah ;

Iwata, Hiroji ;

Cortes, Javier ;

De laurentiis, Michele ;

Jiang, Zefei ;

Arteaga, Carlos L. ;

Jonat, Walter ;

Clemons, Mark ;

Ito, Yoshinori ;

Awada, Ahmad ;

Chia, Stephen ;

Jagiello-Gruszfeld, Agnieszka ;

Pistilli, Barbara ;

Tseng, Ling-Ming ;

Hurvitz, Sara ;

Masuda, Norikazu ;

Takahashi, Masato ;

Vuylsteke, Peter ;

Hachemi, Soulef ;

Dharan, Bharani ;

Di Tomaso, Emmanuelle ;

Urban, Patrick ;

Massacesi, Cristian ;

Campone, Mario .

LANCET ONCOLOGY, 2017, 18 (07) :904-916

[4] 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology [J].

Beaufils, Florent ;

Cmiljanovic, Natasa ;

Cmiljanovic, Vladimir ;

Bohnacker, Thomas ;

Melone, Anna ;

Marone, Romina ;

Jackson, Eileen ;

Zhang, Xuxiao ;

Sele, Alexander ;

Borsari, Chiara ;

Mestan, Jurgen ;

Hebeisen, Paul ;

Hillmann, Petra ;

Giese, Bernd ;

Zvelebil, Marketa ;

Fabbro, Doriano ;

Williams, Roger L. ;

Rageot, Denise ;

Wymann, Matthias P. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (17) :7524-7538

[5] Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment [J].

Brana, Irene ;

Siu, Lillian L. .

BMC MEDICINE, 2012, 10

[6] Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer [J].

Burger, Matthew T. ;

Pecchi, Sabina ;

Wagman, Allan ;

Ni, Zhi-Jie ;

Knapp, Mark ;

Hendrickson, Thomas ;

Atallah, Gordana ;

Pfister, Keith ;

Zhang, Yanchen ;

Bartulis, Sarah ;

Frazier, Kelly ;

Ng, Simon ;

Smith, Aaron ;

Verhagen, Joelle ;

Haznedar, Joshua ;

Huh, Kay ;

Iwanowicz, Ed ;

Xin, Xiaohua ;

Menezes, Daniel ;

Merritt, Hanne ;

Lee, Isabelle ;

Wiesmann, Marion ;

Kaufman, Susan ;

Crawford, Kenneth ;

Chin, Michael ;

Bussiere, Dirksen ;

Shoemaker, Kevin ;

Zaror, Isabel ;

Maira, Sauveur-Michel ;

Voliva, Charles F. .

ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (10) :774-779

[7] The phosphoinositide 3-kinase pathway [J].

Cantley, LC .

SCIENCE, 2002, 296 (5573) :1655-1657

[8] CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway [J].

Chen, Ju ;

Lv, Haining ;

Hu, Jinping ;

Ji, Ming ;

Xue, Nina ;

Li, Chao ;

Ma, Shuanggang ;

Zhou, Qin ;

Lin, Bin ;

Li, Yan ;

Yu, Shishan ;

Chen, Xiaoguang .

CANCER LETTERS, 2016, 381 (02) :391-403

[9] Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design [J].

Cheng, Hengmiao ;

Bagrodia, Shubha ;

Bailey, Simon ;

Edwards, Martin ;

Hoffman, Jacqui ;

Hu, Qiyue ;

Kania, Robert ;

Knighton, Daniel R. ;

Marx, Matthew A. ;

Ninkovic, Sacha ;

Sun, Shaoxian ;

Zhang, Eric .

MEDCHEMCOMM, 2010, 1 (02) :139-144

[10] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

← 1 2 3 4 →