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. 2021 Jul 1:43:128061.
doi: 10.1016/j.bmcl.2021.128061. Epub 2021 Apr 23.

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M King  1 , Sandeep Rana  1 , Sydney P Kubica  1 , Jayapal Reddy Mallareddy  1 , Smitha Kizhake  1 , Edward L Ezell  1 , Muhammad Zahid  2 , Michael J Naldrett  3 , Sophie Alvarez  3 , Henry C-H Law  1 , Nicholas T Woods  4 , Amarnath Natarajan  5
Affiliations

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax

Hannah M King et al. Bioorg Med Chem Lett. .

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.

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Figures

Figure 1.
Figure 1.
Aminopyrazole based PROTACs.
Figure 2.
Figure 2.
Screening of aminopyrazole based PROTACs for CDK9 degradation.
Figure 3.
Figure 3.
Selectivity profile of CDK9 PROTAC 2. Western blot analysis showing dose-dependent (24 h) (A) and time-dependent (1 μM) (B) effects of PROTAC 2 in HEK293 cells. In vitro cell-free IC50 (C) and KD (D) profiling of inhibitor 11 and PROTAC 2, respectively.
Figure 4.
Figure 4.
Mechanism of action of CDK9 PROTAC 2. (A) Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of Pomalidomide and PROTAC 2. (B) Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of Flavopiridol and PROTAC 2. (C) Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of MG132 and PROTAC 2.
Figure 5.
Figure 5.
Kinome and proteome-wide profile of PROTAC 2. (A) Volcano plot of the kinome in HEK293 cells treated with 1μM of PROTAC 2 and incubated for 24 h. (B) Volcano plot of the proteome in MiaPaCa2 cells treated with 1 μM of PROTAC 2 and incubated for 24 h.
Figure 6.
Figure 6.
Synergism studies using BCL inhibitors and PROTAC 2. (A) Structure of Bcl2 inhibitors Navitoclax (ABT-263); Venetoclax (ABT-199); WEHI-539; (B) Growth inhibitory effects of different inhibitors combinations at 5 μM, (C) Combination index (Cl) values for the three Bcl2 inhibitors and PROTAC 2 combinations.
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