Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Review An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers Tahir Ali Chohan a , Aisha Qayyum b , Kanwal Rehman c , Muhammad Tariq d , Muhammad Sajid Hamid Akash e, ⁎ a Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan b Department of Paediatrics Medicine, Sabzazar Hospital, Lahore, Pakistan c Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan d Faculty of Pharmacy & Alternative Medicine, The Islamia University of Bahawalpur, Pakistan e Department of Pharmaceutical Chemistry, Government College University Faisalabad, Pakistan ARTICLE INFO Keywords: CDK Mutagenesis Anticancer Metastatic cancer Hyperproliferation ABSTRACT Cancer denotes a pathological manifestation that is characterized by hyperproliferation of cells. It has antici- pated that a better understanding of disease pathogenesis and the role of cell-cycle regulators may provide an opportunity to develop an effective cancer therapeutic agents. Specifically, the cyclin-dependent kinases (CDKs) which regulate the transition of cell-cycle through different phases; have been identified as fundamental targets for therapeutic advances. It is an evident from experimental studies that several events leading to tumor growth occur by exacerbation of CDK4/CDK6 in G1-phase of cell division cycle. Additionally, the characteristics of S- and G2/M-phase regulated by CDK1/CDK2 are pivotal events that may lead to abrupt the cell division. Although, previously reported CDK inhibitors have shown remarkable results in pre-clinical studies, but have not yielded appreciable clinical results yet. Therefore, the development of clinically potent CDK inhibitors has remained to be a challenging task. However, continuous efforts has led to the development of some novel CDKs inhibitors that have emerged as a potent strategy for the treatment of advanced cancers. In this article, we have sum- marized the role of CDKs in cell-cycle regulation and tumorigenesis and recent advances in the development of CDKs inhibitors as a promising therapy for the treatment of advanced cancer. In addition, we have also per- formed a comparison of crystallographic studies to get valuable insight into the interaction mode differences of inhibitors, binding to CDK isoforms with apparently similar binding sites. The knowledge of ligand-specific recognition towards a particular CDK isoform may be applied as a key tool in future for the designing of isoform- specific inhibitors. 1. Introduction Cancer has remained one of the major medical apprehensions and a leading cause of mortality worldwide [1,2]. Although, survival rates for certain cancers have slightly increased during the last half-century due to early diagnosis and the development of innovative therapies, the successful treatment for advanced stage cancers still remains to be elucidated due to lack of effective treatment strategies [3]. Clinical evidences have shown that almost 80% of cancer mortality is attributed to lack of early diagnosis [4,5]. Advanced cancers are the most difficult challenges for patients and clinicians because these cancers have not yet shown much improvement in prognosis or therapy [6]. Conven- tional treatment modalities (i.e. radiotherapy and chemotherapy) for advanced cancers have been found to destroy the normal cells along with malignant cells in an indiscriminate manner, leading to severe toxicities with modest improvements [7]. Targeted therapy via kinase inhibition is one of the major modalities of cancer treatment that is progressing in the medical treatment of advanced cancers [8]. https://doi.org/10.1016/j.biopha.2018.08.116 Received 18 May 2018; Received in revised form 11 August 2018; Accepted 23 August 2018 Abbreviations: CDK, cyclin dependent kinase; CDK4/6, cyclin dependent kinase 4 and 6; cdc, cell division cycle; CDC25C, cell division cycle 25 homolog; Ser/Thr, serine/ threonine; kDa, kilodaltons (molecular weight); Cip/Kip, CDK interacting protein/kinase inhibitory protein; CKIs, cyclin-dependent kinases inhibitors; CGB, cyclin binding groove; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; HTS, high throughput screening; pRb, retinoblastoma protein; NSCLC, non-small-cell lung carcinoma; SAR, structure activity relationship; ECG, electrocardiogram; FDA, US Food and Drug Administration; HER2, human epidermal receptor 2; HR, hormone receptor; ER, estrogen receptor ⁎ Corresponding author. E-mail address: sajidakash@gcuf.edu.pk (M.S.H. Akash). Biomedicine & Pharmacotherapy 107 (2018) 1326–1341 0753-3322/ © 2018 Published by Elsevier Masson SAS. T