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Review
. 2022 Sep;32(9):1003-1026.
doi: 10.1080/13543776.2022.2116311. Epub 2022 Sep 1.

Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins

Pratik Pal  1 , Peiyi Zhang  1 , Saikat K Poddar  1 , Guangrong Zheng  1
Affiliations
Review

Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins

Pratik Pal et al. Expert Opin Ther Pat. 2022 Sep.

Abstract

Introduction: The anti-apoptotic BCL-2 family proteins, such as BCL-2, BCL-XL, and MCL-1, are excellent cancer therapeutic targets. The FDA approval of BCL-2 selective inhibitor venetoclax in 2016 validated the strategy of targeting these proteins with BH3 mimetic small molecule inhibitors.

Areas covered: This review provides an overview of the patent literature between 2016 and 2021 covering inhibitors and PROTACs of the anti-apoptotic BCL-2 proteins.

Expert opinion: Since the FDA approval of venetoclax, tremendous efforts have been made to develop its analogues with improved drug properties. These activities will likely result in new drugs in coming years. Significant progress on MCL-1 inhibitors has also been made, with multiple compounds entering clinical trials. However, MCL-1 inhibition could cause on-target toxicity to normal tissues especially the heart. Similar issue exists with BCL-XL inhibitors, which cause on-target platelet toxicity. To overcome this issue, several strategies have been applied, including prodrug, dendrimer-based drug delivery, antibody-drug conjugate (ADC), and proteolysis targeting chimera (PROTAC); and amazingly, each of these approaches has resulted in a drug candidate entering clinical trials. We envision technologies like ADC and PROTAC could also be utilized to increase the therapeutic index of MCL-1 inhibitors.

Keywords: Apoptosis; BCL-2 protein family; BH3 mimetics; PROTACs; cancer therapy; protein–protein interactions.

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Conflict of interest statement

Declaration of Interest

P Pal, P Zhang, and G Zheng disclose inventorship of reviewed BCL-XL/BCL-2 PROTAC filings. G Zheng is a co-founder and shareholder of Dialectic Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Intrinsic apoptotic signalling pathway regulated by BCL-2 family of proteins.
Figure 2.
Figure 2.
Structures of ABT-737, ABT-263, and ABT-199
Figure 3.
Figure 3.
Structures of general formula A, APG-2575, and compound 1 (University of Michigan/Ascentage Pharma)
Figure 4.
Figure 4.
Structures of general formula B and compounds 2, 3, 4, 5, and 6 (BeiGene)
Figure 5.
Figure 5.
Structures of general formula C and compound 7 (Centaurus Biopharma)
Figure 6.
Figure 6.
Structures of general formula D and compound 8 (Prelude Therapeutics)
Figure 7.
Figure 7.
Structures of general formula E and compounds 9 and 10 (Fochon Pharmaceuticals)
Figure 8.
Figure 8.
Structures of general formula F and inhibitor 11 (Chia Tai Tianqing)
Figure 9.
Figure 9.
Structures of general formula G and compound 12 (Shenzhen TargetRx)
Figure 10.
Figure 10.
Structures of general formula H and compounds 13, 14, and 15 (Guangzhou Lupeng)
Figure 11.
Figure 11.
Structures of A1210477, S63845, and VU661013
Figure 12.
Figure 12.
Structures of general formula I, MIK665, compounds 16, 17 and 18, and co-crystal structure of 18 in complex with MCL-1 (Les Laboratories Servier & Vernalis)
Figure 13.
Figure 13.
Structures of general formula J, MIK665, compounds 19, 20 and 21, and co-crystal structure of 18 in complex with MCL-1 (Abbvie)
Figure 14.
Figure 14.
Structures of general formula K, AMG-176, and AMG-397 (Amgen)
Figure 15.
Figure 15.
Structures of general formula L, compounds 21, 22, 23, 24, and 25, AZD5991, and co-crystal structures of 21 and 24 in complexes MCL-1 (AstraZeneca)
Figure 16.
Figure 16.
Structures of general formulas M1, M2, and N, and compounds 28, 29 and 30 (Janssen)
Figure 17.
Figure 17.
Structures of general formulas O and P, and compounds 31 and 32 (Gilead)
Figure 18.
Figure 18.
Structures of general formulas Q and R, and compounds 33 and 34 (Ascentage Pharma)
Figure 19.
Figure 19.
Structures of general formulas S and T, and compounds 35 and 36 (Prelude Therapeutics)
Figure 20.
Figure 20.
Structures of general formula U and compounds 37 and 38 (California Institute of Technology)
Figure 21.
Figure 21.
Structures of general formulas V, W, and X, and compounds 39, 40, 41, and 42
Figure 22.
Figure 22.
Mechanism of PROTAC mediated protein degradation
Figure 23.
Figure 23.
Structures of general formula Y, A-1155463, A-1331852, and PROTACs 43 and DT2216 (Dialectic Therapeutics)
Figure 24.
Figure 24.
Structures of PROTACs 44 and 45 (University of Florida)
Figure 25.
Figure 25.
Structures of general formula Z and PROTACs 46 and 47 (Recurium)
Figure 26.
Figure 26.
Structures of ABT-199, ABT-263, compound 48, and PROTAC 49 (Shanghai Tech University and Fudan University)
Figure 27.
Figure 27.
Structures of PROTACs 50, 51, 52, 52, and dMCL1-2
See this image and copyright information in PMC

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