Structure-Guided Rescaffolding of Selective Antagonists of BCL-X<sub>L</sub>

Koehler, Michael F. T.; Bergeron, Philippe; Choo, Edna F.; Lau, Kevin; Ndubaku, Chudi; Dudley, Danette A.; Gibbons, Paul; Sleebs, Brad E.; Rye, Carl S.; Nikolakopoulos, George; Bui, Chinh T.; Kulasegaram, S.; Kersten, Wilhelmus J A; Smith, Brian J.; Czabotar, P.E.; Colman, Peter M.; Huang, David C.S.; Baell, Jonathan B.; Watson, Keith G.; Hasvold, Lisa; Tao, Zhi‐Fu; Wang, Le; Souers, Andrew J.; Elmore, Steven W.; Flygare, John A.; Fairbrother, Wayne J.; Lessène, Guillaume

doi:10.1021/ml500030p

Cited by 36 publications

(36 citation statements)

References 20 publications

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“…The recent development of BCL-X L -specific BH3 mimetic compounds 25 , 26 , 27 enabled us to determine the combined effect of BCL-X L , BCL-2 and MCL-1 inhibition on the megakaryocyte lineage in vivo . Bcl2 Pf4Δ/Pf4Δ Mcl1 Pf4Δ/Pf4Δ double knockout and control littermates were treated with a single dose of the BCL-X L -selective antagonist A-1155463.7 (A-463, 5 mg/kg).…”

Section: Resultsmentioning

confidence: 99%

BCL-2 is dispensable for thrombopoiesis and platelet survival

et al. 2015

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Navitoclax (ABT-263), an inhibitor of the pro-survival BCL-2 family proteins BCL-2, BCL-XL and BCL-W, has shown clinical efficacy in certain BCL-2-dependent haematological cancers, but causes dose-limiting thrombocytopaenia. The latter effect is caused by Navitoclax directly inducing the apoptotic death of platelets, which are dependent on BCL-XL for survival. Recently, ABT-199, a selective BCL-2 antagonist, was developed. It has shown promising anti-leukaemia activity in patients whilst sparing platelets, suggesting that the megakaryocyte lineage does not require BCL-2. In order to elucidate the role of BCL-2 in megakaryocyte and platelet survival, we generated mice with a lineage-specific deletion of Bcl2, alone or in combination with loss of Mcl1 or Bclx. Platelet production and platelet survival were analysed. Additionally, we made use of BH3 mimetics that selectively inhibit BCL-2 or BCL-XL. We show that the deletion of BCL-2, on its own or in concert with MCL-1, does not affect platelet production or platelet lifespan. Thrombocytopaenia in Bclx-deficient mice was not affected by additional genetic loss or pharmacological inhibition of BCL-2. Thus, BCL-2 is dispensable for thrombopoiesis and platelet survival in mice.

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Section: Resultsmentioning

confidence: 99%

BCL-2 is dispensable for thrombopoiesis and platelet survival

et al. 2015

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“…ABT199 is currently in phase 1 trials for CLL, and preliminary results look very promising, with response rates of >80% (2014a). BCL-xL-selective inhibitors (e.g., compound 14, Figure 4) have also been developed, with the aim of treating solid tumors while avoiding the lymphocytic effects of BCL2 (Koehler et al, 2014). The L-shaped BCL-xL-selective series has a distinct binding mode from ABT-199 and appears to be buried more deeply in the peptide-binding groove.…”

Section: Secondary Structure Epitopes: α-Helix β-Sheet or Extended Pmentioning

confidence: 99%

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

Arkin

Tang

Wells

2014

Chemistry & Biology

905

894

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Summary The past twenty years have seen many advances in our understanding of protein-protein interactions (PPI) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of ‘lead-like’ or ‘drug-like’ molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery - structure, computation, screening, and biomarkers. PPI become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last ten years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.

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“…Several BCL-XL inhibitors have been designed and the first specific inhibitor, WEHI-539, binds to BCL-XL with high selectivity and affinity [152]. Since then, further efforts led to the design of A-1155463 and A-1331852, two far more potent inhibitors of which the latter is also orally bio-available [153,154]. Studies show promise for these inhibitors alone and in combination for treatment of solid tumors [154,155].…”

Section: Bh3 Mimetics: Pushing the Apoptotic Blockmentioning

confidence: 99%

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

Ramesh

Medema

2020

Apoptosis

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Apoptosis is a form of programmed cell death that is essential for tissue homeostasis. Deregulation of the balance between proliferation and apoptosis contributes to tumor initiation. Particularly in the colon where apoptosis is a crucial process in intestinal turnover, inhibition of apoptosis facilitates transformation and tumor progression. The BCL-2 family of proteins are key regulators of apoptosis and have been implicated in colorectal cancer (CRC) initiation, progression and resistance to therapy. In this review we outline the current knowledge on the BCL-2 family-regulated intrinsic apoptosis pathway and mechanisms by which it is de-regulated in CRC. We further review BH3 mimetics as a therapeutic opportunity to target this pathway and evaluate their potential for CRC treatment.

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Structure-Guided Rescaffolding of Selective Antagonists of BCL-X_L

Cited by 36 publications

References 20 publications

BCL-2 is dispensable for thrombopoiesis and platelet survival

BCL-2 is dispensable for thrombopoiesis and platelet survival

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

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Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

Cited by 36 publications

References 20 publications

BCL-2 is dispensable for thrombopoiesis and platelet survival

BCL-2 is dispensable for thrombopoiesis and platelet survival

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

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Structure-Guided Rescaffolding of Selective Antagonists of BCL-X_L