~ 15 ~ Journal of Pharmacognosy and Phytochemistry 2018; SP6: 15-18 E-ISSN: 2278-4136 P-ISSN: 2349-8234 JPP 2018; SP6: 15-18 Priyanka V Bandivadekar Konkangyanpeeth Rahul Dharkar College of pharmacy, Karjat, Maharashtra, India Vrushali Neve Konkangyanpeeth Rahul Dharkar College of pharmacy, Karjat, Maharashtra, India Poonam Patil Konkangyanpeeth Rahul Dharkar College of pharmacy, Karjat, Maharashtra, India Correspondence Priyanka V Bandivadekar Konkangyanpeeth Rahul Dharkar College of pharmacy, Karjat, Maharashtra, India (Special Issue- 6) Innovation development and standardization of Novel Herbal Formulation (September 24-25, 2018) Cdk 4/6 inhibitors revolutionized breast cancer therapy Priyanka V Bandivadekar, Vrushali Neve and Poonam Patil DOI: https://doi.org/10.22271/phyto.2018.v7.isp6.1.04 Abstract The cyclin-CDK inhibitors of the Cip/Kip family p21Cip1, p27Kip1, and p57Kip2 have emerged as multifaceted proteins with functions beyond cell cycle regulation. They are used to treat cancers by preventing over proliferation of cancer cells. In metazoans, two CKI gene families have been defined based on their evolutionary origins, structure, and CDK specificities. A vast body of literature has described the importance of p21, p27, and p57 in restraining proliferation during development, differentiation, and response to cellular stresses, although each has specific biological functions that distinguish it from the other family members. Thus, different anti-proliferative signals tend to cause elevated expression of only a subset of the Cip/Kip proteins. Following a recent and detailed review on the subject. We concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors will be discussed. Keywords: cyclin-CDK, ATP-competitive inhibitors, ATP non-competitive, metazone Introduction Breast Cancer (BC) is the most common cancer type in women. It is estimated that it will be responsible for 40,450 deaths in the US in 2016, representing the second cause of cancer- related death after lung cancer [1] . Amongst novel possible therapeutical targets, proteins involved in the control of the cell cycle attracted a lot of interest in the last 10 years: cyclins and cyclin-dependent kinases (CDKs) were firstly discovered in yeast and then in humans [2] . In normal tissues, cell proliferation is tightly regulated by the cell cycle machinery, a group of proteins that controls a cell’s orderly procession from one phase of the cell cycle to the next. In breast cancer, much attention has been given to particular members of the cell cycle machinery. The D-type cyclins and their partner kinases, cyclin-dependent kinase 4 (CDK4) and CDK6. Indeed, a wealth of preclinical research has shown that tumor cell proliferation in many breast cancers is underpinned by hyperactivity of the cyclin D–CDK4/6 axis, making pharmacological blockade of this axis an attractive therapeutic strategy [3-5] . First-generation CDK inhibitors tended to be less specific, targeting other CDKs in a broad fashion and were associated with chemotherapy-like toxicities and unacceptable safety profiles. More recently, a new generation of very specific CDK 4/6 inhibitors have been developed [6-7] . Mechanism of cyclind1–CDK4/6–RB pathway Potent, selective, orally bioavailable inhibitors of CDK4/6 have only become available as cancer therapeutics in the last decade. By directly blocking the activity of the cyclin D– CDK4/6 holoenzyme, these agents act to restrain proliferation of sensitive tumor cells, in particular preventing cell cycle progression from the G1 to the S phase of the cell cycle (see below and Figure 1). In sensitive cells, CDK4/6 inhibition typically induces a phenotype resembling cellular senescence [8] , consistent with the critical role of the retinoblastoma (RB) tumor suppressor in mediating senescence [9] .