Research Article

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

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Xuanyi Li

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

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Hequan Yao

**Author for correspondence:

E-mail Address: hyao@cpu.edu.cn

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

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Kejiang Lin

*Author for correspondence:

E-mail Address: link@cpu.edu.cn

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

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Published Online:13 Nov 2019https://doi.org/10.4155/fmc-2019-0062

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Abstract

Aim: CDK4/6 have critical roles in the early stage of the cell cycle. CDK2 acts later in the cell cycle and has a considerably broader range of protein substrates, some of which are essential for normal cell proliferation. Therefore, increasing the selectivity of cyclin-dependent kinase (CDK) inhibitors is critical. Methodology: In this study, we construct a versatile, specific CDK4 pharmacophore model that not only matches well with 8119 of the reported 9349 CDK4/6 inhibitors but also differentiates from the CDK2 pharmacophore. Results & Conclusion: we demonstrate the activity and selectivity determinants of CDK4/6 selective inhibitors based on the CDK4 pharmacophore model. Finally, we propose the future optimization strategy for CDK4/6 selective inhibitors, providing a theoretical basis for further research and development of CDK4/6 selective inhibitors.

Graphical abstract

According to our CDK4 feature model, four decisive factors (capability as a hydrogen bond donor and acceptor, hydrophobicity, electrostatic potential) are highly desirable for potent inhibitory activity and selectivity. At present, most CDK4/6 selective inhibitors have similar skeletons and branches. The structure–activity relationship revealed by the 3D quantitation structure–activity relationships pharmacophore study is illustrated in the following picture. The key hydrogen bond with the hinge region (Val96) is indispensable for activity, although it does not play a major role in selectivity. Along the dotted line, we can design a hetero atom-containing group to form a hydrogen bond interaction with the Lys35^CDK4 at the bottom of the binding site. Selectivity is not the effect of a particular residue, but a cumulative effect. A unique hydrogen bonding between the side chain of His95 and the CDK4 inhibitor could improve the selectivity. There is no steric hindrance (Thr102) at the entrance of the binding pocket of CDK4, and the branch A of the scaffold could be designed to be larger such that it is appropriately positively charged and extends to the ‘top’ of the binding site (Asp99) to improve selectivity.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 12, No. 2

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Received 5 March 2019

Accepted 23 October 2019

Published online 13 November 2019

Published in print January 2020

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To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/suppl/10.4155/fmc-2019-0062

Financial & competing interest disclosure

This work was supported by funds from the National Key R&D Program of China (2018YFC0311005), ‘Double First-Class’ University Project, China (CPU2018GY15) and the Key Laboratory of Spectrochemical Analysis & Instrumentation (Xiamen University), Ministry of Education, China (SCAI1802). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors thank American Journal Experts (AJE), NC, USA, for their English language editing.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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Development and strategies of CDK4/6 inhibitors

Abstract

Graphical abstract

References