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8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode.

Carbain B, Paterson DJ, Anscombe E, Campbell AJ, Cano C, Echalier A, Endicott JA, Golding BT, Haggerty K, Hardcastle IR, Jewsbury PJ, Newell DR, Noble ME, Roche C, Wang LZ, Griffin RJ
J Med Chem 57 56-70 (2014)
Related entries: 4cfm, 4cfn, 4cfu, 4cfv, 4cfw, 4cfx

Cited: 7 times
EuropePMC logo PMID: 24304238

Abstract

Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

Articles - 1w8c mentioned but not cited (1)

  1. Protein surface characterization using an invariant descriptor. Abu Deeb Z, Adjeroh DA, Jiang BH. Int J Biomed Imaging 2011 918978 (2011)


Articles citing this publication (6)

  1. Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. Anthony NG, Baiget J, Berretta G, Boyd M, Breen D, Edwards J, Gamble C, Gray AI, Harvey AL, Hatziieremia S, Ho KH, Huggan JK, Lang S, Llona-Minguez S, Luo JL, McIntosh K, Paul A, Plevin RJ, Robertson MN, Scott R, Suckling CJ, Sutcliffe OB, Young LC, Mackay SP. J. Med. Chem. 60 7043-7066 (2017)
  2. Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead. Wu F, Zhuo L, Wang F, Huang W, Hao G, Yang G. iScience 23 101179 (2020)
  3. In silico 3D structure modeling and inhibitor binding studies of human male germ cell-associated kinase. Tanneeru K, Balla AR, Guruprasad L. J. Biomol. Struct. Dyn. 33 1710-1719 (2015)
  4. Molecular Modeling and Design Studies of Purine Derivatives as Novel CDK2 Inhibitors. Zhang G, Ren Y. Molecules 23 (2018)
  5. Scaffold Hopping Approach to a New Series of Pyridine Derivatives as Potent Inhibitors of CDK2. Xu X, Yao Q. Arch. Pharm. (Weinheim) 349 224-231 (2016)
  6. Unsubstituted Bambusurils: Post-Macrocyclization Modification of Versatile Intermediates. Havel V, Sadilová T, Šindelář V. ACS Omega 3 4657-4663 (2018)


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