Selective degradation of CDK6 by a palbociclib based PROTAC

Sandeep Rana; Mourad Bendjennat; Smit Kour; Hannah M. King; Smitha Kizhake; Muhammad Zahid; Amarnath Natarajan

doi:10.1016/j.bmcl.2019.03.035

Selective degradation of CDK6 by a palbociclib based PROTAC

Sandeep Rana, Mourad Bendjennat, Smit Kour, Hannah M. King, Smitha Kizhake, Muhammad Zahid, Amarnath Natarajan

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

Original language	English (US)
Pages (from-to)	1375-1379
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2019.03.035
State	Published - Jun 1 2019

Keywords

CDK6
CDK6 degrader
PROTAC
Palbociclib

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2019.03.035

Cite this

@article{43df0a99960f4e2a92c7d3acd0074536,

title = "Selective degradation of CDK6 by a palbociclib based PROTAC",

abstract = "Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.",

keywords = "CDK6, CDK6 degrader, PROTAC, Palbociclib",

author = "Sandeep Rana and Mourad Bendjennat and Smit Kour and King, {Hannah M.} and Smitha Kizhake and Muhammad Zahid and Amarnath Natarajan",

note = "Funding Information: This work was supported in part by NIH grants CA197999, and CA036727. We would like to thank Ed Ezell for NMR, and the Natarajan lab members for helpful discussions. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = jun,

day = "1",

doi = "10.1016/j.bmcl.2019.03.035",

language = "English (US)",

volume = "29",

pages = "1375--1379",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "11",

}

TY - JOUR

T1 - Selective degradation of CDK6 by a palbociclib based PROTAC

AU - Rana, Sandeep

AU - Bendjennat, Mourad

AU - Kour, Smit

AU - King, Hannah M.

AU - Kizhake, Smitha

AU - Zahid, Muhammad

AU - Natarajan, Amarnath

N1 - Funding Information: This work was supported in part by NIH grants CA197999, and CA036727. We would like to thank Ed Ezell for NMR, and the Natarajan lab members for helpful discussions. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

AB - Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

KW - CDK6

KW - CDK6 degrader

KW - PROTAC

KW - Palbociclib

UR - http://www.scopus.com/inward/record.url?scp=85063488085&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063488085&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2019.03.035

DO - 10.1016/j.bmcl.2019.03.035

M3 - Article

C2 - 30935795

AN - SCOPUS:85063488085

SN - 0960-894X

VL - 29

SP - 1375

EP - 1379

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 11

ER -

Selective degradation of CDK6 by a palbociclib based PROTAC

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this