Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

被引：336

作者：

Marsilje, Thomas H. ^{[1
]}

Pei, Wei ^{[1
]}

Chen, Bei ^{[1
]}

Lu, Wenshuo ^{[1
]}

Uno, Tetsuo ^{[1
]}

Jin, Yunho ^{[1
]}

Jiang, Tao ^{[1
]}

Kim, Sungjoon ^{[1
]}

Li, Nanxin ^{[1
]}

Warmuth, Markus ^{[1
]}

Sarkisova, Yelena ^{[1
]}

Sun, Frank ^{[1
]}

Steffy, Auzon ^{[1
]}

Pferdekamper, AnneMarie C. ^{[1
]}

Li, Allen G. ^{[1
]}

Joseph, Sean B. ^{[1
]}

Kim, Young ^{[1
]}

Liu, Bo ^{[1
]}

Tuntland, Tove ^{[1
]}

Cui, Xiaoming ^{[1
]}

Gray, Nathanael S. ^{[1
]}

Steensma, Ruo ^{[1
]}

Wan, Yongqin ^{[1
]}

Jiang, Jiqing ^{[1
]}

Chopiuk, Greg ^{[1
]}

Li, Jie ^{[1
]}

Gordon, W. Perry ^{[1
]}

Richmond, Wendy ^{[1
]}

Johnson, Kevin ^{[1
]}

Chang, Jonathan ^{[1
]}

Groessl, Todd ^{[1
]}

He, You-Qun ^{[1
]}

Phimister, Andrew ^{[1
]}

Aycinena, Alex ^{[1
]}

Lee, Christian C. ^{[1
]}

Bursulaya, Badry ^{[1
]}

Karanewsky, Donald S. ^{[1
]}

Seidel, H. Martin ^{[1
]}

Harris, Jennifer L. ^{[1
]}

Michellys, Pierre-Yves ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 14期

关键词：

RECEPTOR TYROSINE KINASE; NON-HODGKINS-LYMPHOMA; CELL LUNG-CANCER; EXPERIMENTAL-MODELS; ANTITUMOR-ACTIVITY; DRUG DISCOVERY; SOLID TUMORS; C-MET; GENE; IDENTIFICATION;

D O I：

10.1021/jm400402q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

引用

页码：5675 / 5690

页数：16

共 20 条

[1] Discovery of N-{2-Methoxy-4-14-(4-methylpiperazin-1-yl)piperidin-l-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor
Iikubo, Kazuhiko
Kondoh, Yutaka
Shimada, Itsuro
Matsuya, Takahiro
Mori, Kenichi
Ueno, Yoko
Okada, Minoru
CHEMICAL & PHARMACEUTICAL BULLETIN, 2018, 66 (03) : 251 - 262
[2] 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-((4-methylpiperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-2,4-diamine (WY-135), a novel ALK inhibitor, induces cell cycle arrest and apoptosis through inhibiting ALK and its downstream pathways in Karpas299 and H2228 cells
Han, Mengting
Shen, Jiwei
Wang, Lijing
Wang, Yu
Zhai, Xin
Li, Yao
Liu, Meiqiao
Li, Zengqiang
Zuo, Daiying
Wu, Yingliang
CHEMICO-BIOLOGICAL INTERACTIONS, 2018, 284 : 24 - 31
[3] Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity
Wang, Yang
Chen, Xing
Yan, Yaoyao
Zhu, Xiaochen
Liu, Mingming
Liu, Xinhua
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (06) : 3327 - 3347
[4] Discovery of 5 Chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a Novel Inhibitor of the Jak/Stat Pathway
Ioannidis, Stephanos
Lamb, Michelle L.
Wang, Tao
Almeida, Lynsie
Block, Michael H.
Davies, Audrey M.
Peng, Bo
Su, Mei
Zhang, Hai-Jun
Hoffmann, Ethan
Rivard, Caroline
Green, Isabelle
Howard, Tina
Pollard, Hannah
Read, Jon
Alimzhanov, Marat
Bebernitz, Geraldine
Bell, Kirsten
Ye, Minwei
Huszar, Dennis
Zinda, Michael
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (01) : 262 - 276
[5] Modeling the anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Activity of (E)-6-chloro-N2-phenyl-N4-(4-Phenyl-5-(Phenyl Diazinyl)-2λ3, 3 λ2- Thiazol-2-yl)-1, 3, 5-Triazine-2,4-Diamine
Benjamin, Innocent
Louis, Hitler
Ekpen, Francis O.
Gber, Terkumbur E. E.
Gideon, Mathias E. E.
Ahmad, Iqrar
Unimuke, Tomsmith O. O.
Akanimo, Nyong P.
Patel, Harun
Eko, Ishegbe J. J.
Simon, Ojima
Agwamba, Ernest C. C.
Ejiofor, Emmanuel U. U.
POLYCYCLIC AROMATIC COMPOUNDS, 2023, 43 (09) : 7942 - 7969
[6] 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-((4-methylpiperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-2,4-diamine (WY-135), a novel ALK inhibitor, induces cell cycle arrest and apoptosis through inhibiting ALK and its downstream pathways in Karpas299 and H2228 cells (vol 284, pg 24, 2018)
Han, Mengting
Shen, Jiwei
Wang, Lijing
Wang, Yu
Zhai, Xin
Li, Yao
Liu, Meiqiao
Gao, Meiqi
Li, Zengqiang
Zuo, Daiying
Wu, Yingliang
CHEMICO-BIOLOGICAL INTERACTIONS, 2022, 356
[7] Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
Chen, Yongfei
Wu, Jiaxin
Wang, Aoli
Qi, Ziping
Jiang, Taoshan
Chen, Cheng
Zou, Fengming
Hu, Chen
Wang, Wei
Wu, Hong
Hu, Zhenquan
Wang, Wenchao
Wang, Beilei
Wang, Li
Ren, Tao
Zhang, Shanchun
Liu, Qingsong
Liu, Jing
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 139 : 674 - 697
[8] Improved Synthesis of the Selective Rho-Kinase Inhibitor 6-Chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidin-2,4-diamine
Schirok, Hartmut
Paulsen, Holger
Kroh, Walter
Chen, Gang
Gao, Ping
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2010, 14 (01) : 168 - 173
[9] Antagonists of the human CCR5 receptor as anti-HIV-1 agents.: Part 4:: Synthesis and structure-activity relationships for 1-[N(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N- (benzyloxycarbonyl)amino)piperidin-1-yl)butanes
Finke, PE
Oates, B
Mills, SG
MacCoss, M
Malkowitz, L
Springer, MS
Gould, SL
DeMartino, JA
Carella, A
Carver, G
Holmes, K
Danzeisen, R
Hazuda, D
Kessler, J
Lineberger, J
Miller, M
Schleif, WA
Emini, EA
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (18) : 2475 - 2479
[10] STRUCTURE-ACTIVITY RELATIONSHIP OF N-[2-(DIMETHYLAMINO)-6-[3-(5-METHYL-4-PHENYL-1H-IMIDAZOL-1-YL)PROPOXY]PHENYL]-N'-PENTYLUREA AND ANALOGS - NOVEL POTENT INHIBITORS OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE WITH ANTIATHEROSCLEROTIC ACTIVITY
KIMURA, T
TAKASE, Y
HAYASHI, K
TANAKA, H
OHTSUKA, I
SAEKI, T
KOGUSHI, M
YAMADA, T
FUJIMORI, T
SAITOU, I
AKASAKA, K
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (11) : 1630 - 1640

← 1 2 →