BCL2 binds BCL2 antagonists

Stable Identifier
Reaction [binding]
Homo sapiens
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Apoptosis is governed by two pathways that ultimately lead to cell death. The extrinsic pathway is activated in response to external signalling proteins and is tightly regulated by the Bcl-2 superfamily of proteins. For a cell in its resting state, BCL family members, acting as suppressors, bind to effectors and activators of apoptosis to suppress their activity. One of the hallmarks of cancer is to evade apoptosis. Changes in the anti-apoptotic protein BCL2 is a hallmark of B-cell lymphoma. BCL2 antagonists are used for B-cell lymphomas and acute leukemias (McBride et al. 2019, Adams et al. 2019, Merino et al. 2018).

The first synthetic BH-3 mimetic was ABT-737, a small-molecule that binds with high affinity to BCL-2 family members and was shown to induce apoptosis in some lymphoma cell lines (Paoluzzi et al. 2008, Volger et al. 2008). However, ABT-737 shows poor bioavailability. Navitoclax (ABT-263) is a BH3 mimetic which antagonises the action of Bcl-2 family proteins. It is a re-engineered drug from ABT-737 and shows much higher bioavailability than ABT-737 (Bruncko et al. 2007). Navitoclax induces complete tumour regression in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia (Tse et al. 2008). Venetoclax (ABT-199) is a BH3 mimetic that selectively targets BCL2 and is the only BCL2 antagonist approved for patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (Souers et al. 2013). Unlike its predecessors, venetoclax is highly selective for BCL2 (Pan et al. 2014).
Literature References
PubMed ID Title Journal Year
18591385 The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies

O'Connor, OA, Gonen, M, Scotto, L, Manova, K, Heaney, ML, Bhagat, G, Gardner, JR, Furman, RR, Paoluzzi, L, Gueorguiev, VD

Blood 2008
23291630 ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

Souers, AJ, Xiao, Y, Oleksijew, A, Nimmer, PM, Seymour, JF, Sampath, D, Zhang, H, Khaw, SL, Tahir, SK, Mitten, MJ, Xue, JC, Enschede, SH, Fairbrother, WJ, Boghaert, ER, Hymowitz, SG, Huang, DC, Phillips, DC, Tse, C, Humerickhouse, RA, Marsh, KC, Rosenberg, SH, Ding, H, Leverson, JD, Lee, J, Jin, S, Chen, J, Park, CM, Lam, LT, Wendt, MD, Catron, ND, Park, CH, Dayton, BD, Mason, KD, Sullivan, GM, Elmore, SW, Maecker, HL, Smith, ML, Roberts, AW, Kovar, PJ, Ackler, SL

Nat. Med. 2013
17256834 Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL

Oltersdorf, T, Ding, H, Wang, X, Nimmer, PM, Park, CM, Kunzer, A, Joseph, MK, Wendt, MD, Shoemaker, AR, Petros, AM, Zhang, H, Martineau, D, Ng, SC, Song, X, Elmore, SW, Fesik, SW, Mitten, M, Oost, TK, Rosenberg, SH, Bruncko, M, McClellan, WJ, Belli, BA

J. Med. Chem. 2007
24346116 Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia

Debose, L, Galinsky, I, Kantarjian, H, Bucci, D, Mu, H, Stone, RM, Andreeff, M, Haferlach, T, Zweidler-McKay, P, Marcucci, G, Gaidzik, VI, Döhner, H, Borthakur, G, Leverson, JD, Ryan, J, Golfman, LS, Han, L, Park, E, Benito, JM, Hogdal, LJ, Harutyunyan, KG, Pan, R, Hu, J, Müschen, M, Letai, AG, Konopleva, M, Cortes, J, Ruvolo, PP, Schindela, S, Newman, R, Ruvolo, V, Deangelo, DJ

Cancer Discov 2014
18309326 A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

Young, KW, Nicotera, P, Butterworth, M, Dyer, MJ, Cohen, GM, Dinsdale, D, Sun, XM, Vogler, M

Cell Death Differ. 2008
18451170 ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor

Yang, X, Xiao, Y, Jin, S, Chen, J, Anderson, MG, Adickes, J, Shoemaker, AR, Zhang, H, Tse, C, Nimmer, P, Johnson, EF, Tahir, SK, Mitten, MJ, Roberts, L, Elmore, SW, Marsh, KC, Rosenberg, SH, Fesik, S

Cancer Res. 2008
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