Literature DB >> 23623490

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.

Xiaojing Wang1, Steven Magnuson, Rich Pastor, Eric Fan, Huiyong Hu, Vickie Tsui, Wei Deng, Jeremy Murray, Micah Steffek, Heidi Wallweber, John Moffat, Jason Drummond, Grace Chan, Eric Harstad, Allen J Ebens.   

Abstract

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.
Copyright © 2013 Elsevier Ltd. All rights reserved.

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Year:  2013        PMID： 23623490     DOI： 10.1016/j.bmcl.2013.04.020

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  7 in total

1.  Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors.

Authors:  Yong Xu; Benjamin G Brenning; Steven G Kultgen; Jason M Foulks; Adrianne Clifford; Shuping Lai; Ashley Chan; Shannon Merx; Michael V McCullar; Steven B Kanner; Koc-Kan Ho
Journal:  ACS Med Chem Lett       Date:  2014-10-22       Impact factor: 4.345

2.  Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

Authors:  Matthew T Burger; Wooseok Han; Jiong Lan; Gisele Nishiguchi; Cornelia Bellamacina; Mika Lindval; Gordana Atallah; Yu Ding; Michelle Mathur; Chris McBride; Elizabeth L Beans; Kristine Muller; Victoriano Tamez; Yanchen Zhang; Kay Huh; Paul Feucht; Tatiana Zavorotinskaya; Yumin Dai; Jocelyn Holash; Joseph Castillo; John Langowski; Yingyun Wang; Min Y Chen; Pablo D Garcia
Journal:  ACS Med Chem Lett       Date:  2013-10-15       Impact factor: 4.345

Review 3.  Targeting the Pim kinases in multiple myeloma.

Authors:  N A Keane; M Reidy; A Natoni; M S Raab; M O'Dwyer
Journal:  Blood Cancer J       Date:  2015-07-17       Impact factor: 11.037

4.  Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions.

Authors:  Badr Jismy; Abdellatif Tikad; Mohamed Akssira; Gérald Guillaumet; Mohamed Abarbri
Journal:  Molecules       Date:  2020-04-28       Impact factor: 4.411

5.  Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing.

Authors:  J H Song; N An; S Chatterjee; E Kistner-Griffin; S Mahajan; S Mehrotra; A S Kraft
Journal:  Oncogene       Date:  2014-09-22       Impact factor: 9.867

6.  Insulin receptor substrate 1 is a substrate of the Pim protein kinases.

Authors:  Jin H Song; Sathish K R Padi; Libia A Luevano; Mark D Minden; Daniel J DeAngelo; Gary Hardiman; Lauren E Ball; Noel A Warfel; Andrew S Kraft
Journal:  Oncotarget       Date:  2016-04-12

7.  Metal-free direct alkylation of unfunctionalized allylic/benzylic sp3 C-H bonds via photoredox induced radical cation deprotonation.

Authors:  Rong Zhou; Haiwang Liu; Hairong Tao; Xingjian Yu; Jie Wu
Journal:  Chem Sci       Date:  2017-04-28       Impact factor: 9.825
  7 in total

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