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The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.

Wrobleski ST, Lin S, Dhar TG, Dyckman AJ, Li T, Pitt S, Zhang R, Fan Y, Doweyko AM, Tokarski JS, Kish KF, Kiefer SE, Sack JS, Newitt JA, Witmer MR, McKinnon M, Barrish JC, Dodd JH, Schieven GL, Leftheris K
Bioorg Med Chem Lett 23 4120-6 (2013)
Related entries: 4kin, 4kip

Cited: 9 times
EuropePMC logo PMID: 23746475

Abstract

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

Articles - 4kiq mentioned but not cited (4)

  1. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, Elcock A, Zhu S. Front Oncol 9 1294 (2019)
  2. Towards good correlation between fragment molecular orbital interaction energies and experimental IC50 for ligand binding: A case study of p38 MAP kinase. Sheng Y, Watanabe H, Maruyama K, Watanabe C, Okiyama Y, Honma T, Fukuzawa K, Tanaka S. Comput Struct Biotechnol J 16 421-434 (2018)
  3. ALADDIN: Docking Approach Augmented by Machine Learning for Protein Structure Selection Yields Superior Virtual Screening Performance. Fan N, Bauer CA, Stork C, de Bruyn Kops C, Kirchmair J. Mol Inform 39 e1900103 (2020)
  4. Network Pharmacology-Based Analysis of the Underlying Mechanism of Huajiao for Pain Relief. Wu M, Du HL, Zhou X, Peng W, Liu L, Zhang Z, Tu H. Evid Based Complement Alternat Med 2021 5526132 (2021)


Reviews citing this publication (3)

  1. Animal models of rheumatoid arthritis: How informative are they? McNamee K, Williams R, Seed M. Eur J Pharmacol 759 278-286 (2015)
  2. Atypical p38 Signaling, Activation, and Implications for Disease. Burton JC, Antoniades W, Okalova J, Roos MM, Grimsey NJ. Int J Mol Sci 22 4183 (2021)
  3. A Comprehensive Structural Overview of p38α Mitogen-Activated Protein Kinase in Complex with ATP-Site and Non-ATP-Site Binders. Astolfi A, Manfroni G, Cecchetti V, Barreca ML. ChemMedChem 13 7-14 (2018)

Articles citing this publication (2)

  1. Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors. Veerman JJN, Bruseker YB, Damen E, Heijne EH, van Bruggen W, Hekking KFW, Winkel R, Hupp CD, Keefe AD, Liu J, Thomson HA, Zhang Y, Cuozzo JW, McRiner AJ, Mulvihill MJ, van Rijnsbergen P, Zech B, Renzetti LM, Babiss L, Müller G. ACS Med Chem Lett 12 555-562 (2021)
  2. OA10 is a novel p38alpha mitogen-activated protein kinase inhibitor that suppresses osteoclast differentiation and bone resorption. Jiang T, Qin A, Shao ZY, Tian B, Zhai ZJ, Li HW, Zhu ZA, Dai KR, Ming HZ, Yu YP, Jiang Q. J Cell Biochem 115 959-966 (2014)


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