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

7 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
Externally published	Yes

Keywords

Aminopyrazole
CDK
Cancer
PROTAC
Venetoclax

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2021.128061

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Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax. / King, Hannah M.; Rana, Sandeep; Kubica, Sydney P.; Mallareddy, Jayapal Reddy; Kizhake, Smitha; Ezell, Edward L.; Zahid, Muhammad ; Naldrett, Michael J.; Alvarez, Sophie; Law, Henry C.H.; Woods, Nicholas T.; Natarajan, Amarnath.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 43, 128061, 01.07.2021.

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

King, Hannah M. ; Rana, Sandeep ; Kubica, Sydney P. ; Mallareddy, Jayapal Reddy ; Kizhake, Smitha ; Ezell, Edward L. ; Zahid, Muhammad ; Naldrett, Michael J. ; Alvarez, Sophie ; Law, Henry C.H. ; Woods, Nicholas T. ; Natarajan, Amarnath. / Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax. In: Bioorganic and Medicinal Chemistry Letters. 2021 ; Vol. 43.

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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.",

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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 = "Funding Information: This work was supported in part by NIH grants CA197999 , CA251151 , GM121316 , and CA036727 . HMK was supported by a UNMC graduate fellowship. We would like to thank the Natarajan lab members for helpful discussions. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

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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

N1 - Funding Information: This work was supported in part by NIH grants CA197999 , CA251151 , GM121316 , and CA036727 . HMK was supported by a UNMC graduate fellowship. We would like to thank the Natarajan lab members for helpful discussions. Publisher Copyright: © 2021 Elsevier Ltd

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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

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Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Abstract

Keywords

ASJC Scopus subject areas

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