Reverse engineering of navitoclax identified a BCL-2–selective inhibitor that does not kill platelets.
Major finding: Reverse engineering of navitoclax identified a BCL-2–selective inhibitor that does not kill platelets.
Concept: Navitoclax blocks the activity of both BCL-2 and BCL-XL, the primary platelet survival factor.
Impact: A selective BCL-2 inhibitor can be used at relatively high doses without causing thrombocytopenia.
Prosurvival BCL-2 family proteins that mediate evasion of apoptosis are often required for cancer cell survival and represent attractive therapeutic targets. The orally bioavailable small molecule navitoclax (ABT-263) inhibits the antiapoptotic activity of the highly related proteins BCL-2 and BCL-XL and has shown clinical activity in BCL-2–dependent hematologic cancers. However, BCL-XL is also a key survival factor for platelets, and BCL-XL inhibition by navitoclax leads to a rapid decrease in circulating platelets, or thrombocytopenia, that limits dosing. Souers and colleagues therefore hypothesized that a selective BCL-2 inhibitor might be used at more effective doses in BCL-2–dependent cancers without on-target thrombocytopenia. Systematic removal or replacement of navitoclax moieties to identify features that increased BCL-2 selectivity led to the discovery of ABT-199, a small molecule with subnanomolar affinity for BCL-2. ABT-199 potently disrupted BCL-2 function and induced apoptotic cell death, particularly in leukemia and lymphoma cells with high BCL-2 expression. Single-agent ABT-199 suppressed growth of several hematologic tumor xenograft models in a dose-dependent manner and potentiated the activity of clinically relevant chemotherapies and immunotherapies such as bendamustine and rituximab. Importantly, ABT-199 was significantly less active against human platelets ex vivo than navitoclax and could be used at much higher doses in dogs without appreciable effects on circulating platelets, suggesting that efficacious plasma concentrations of ABT-199 might be attained without platelet damage. Indeed, in a first-inhuman trial in 3 patients with refractory chronic lymphocytic leukemia, a single dose of ABT-199 induced tumor lysis in all 3 patients with in 24 hours with minimal effects on platelet counts. BCL-2–selective inhibition may therefore be feasible for treatment of BCL-2–dependent cancers and avoid ontarget toxicity associated with inhibition of BCL-XL.
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