Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M. King; Sandeep Rana; Sydney P. Kubica; Jayapal Reddy Mallareddy; Smitha Kizhake; Edward L. Ezell; Muhammad Zahid; Michael J. Naldrett; Sophie Alvarez; Henry C.H. Law; Nicholas T. Woods; Amarnath Natarajan

doi:10.1016/j.bmcl.2021.128061

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M. King, Sandeep Rana, Sydney P. Kubica, Jayapal Reddy Mallareddy, Smitha Kizhake, Edward L. Ezell, Muhammad Zahid, Michael J. Naldrett, Sophie Alvarez, Henry C.H. Law, Nicholas T. Woods, Amarnath Natarajan

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

38 Scopus citations

Abstract

Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC₅₀ = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

Original language	English (US)
Article number	128061
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	43
DOIs	https://doi.org/10.1016/j.bmcl.2021.128061
State	Published - Jul 1 2021

Keywords

Aminopyrazole
CDK
Cancer
PROTAC
Venetoclax

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2021.128061

Cite this

@article{58043ad3a725449488edc5197a3ad4ab,

title = "Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax",

abstract = "Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.",

keywords = "Aminopyrazole, CDK, Cancer, PROTAC, Venetoclax",

author = "King, {Hannah M.} and Sandeep Rana and Kubica, {Sydney P.} and Mallareddy, {Jayapal Reddy} and Smitha Kizhake and Ezell, {Edward L.} and Muhammad Zahid and Naldrett, {Michael J.} and Sophie Alvarez and Law, {Henry C.H.} and Woods, {Nicholas T.} and Amarnath Natarajan",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = jul,

day = "1",

doi = "10.1016/j.bmcl.2021.128061",

language = "English (US)",

volume = "43",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

AU - King, Hannah M.

AU - Rana, Sandeep

AU - Kubica, Sydney P.

AU - Mallareddy, Jayapal Reddy

AU - Kizhake, Smitha

AU - Ezell, Edward L.

AU - Zahid, Muhammad

AU - Naldrett, Michael J.

AU - Alvarez, Sophie

AU - Law, Henry C.H.

AU - Woods, Nicholas T.

AU - Natarajan, Amarnath

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

AB - Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

KW - Aminopyrazole

KW - CDK

KW - Cancer

KW - PROTAC

KW - Venetoclax

UR - http://www.scopus.com/inward/record.url?scp=85105897142&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85105897142&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2021.128061

DO - 10.1016/j.bmcl.2021.128061

M3 - Article

C2 - 33895280

AN - SCOPUS:85105897142

SN - 0960-894X

VL - 43

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 128061

ER -

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this