GX15–070MS, a synthetic small molecule induces apoptosis in vitro and in vivo in chronic lymphocytic leukemia

Abstract

3167 Chronic lymphocytic leukemia (CLL) B cells express high levels of anti-apoptotic proteins of the Bcl-2 family, such as Mcl-1, Bcl-XL, and Bcl-2. These proteins enhance the resistance of CLL cells to spontaneous and/or drug-induced apoptosis primarily by interacting with, and antagonizing the activity of mitochondria membrane pro-apoptotic proteins such as Bax and Bik. These interactions are governed by the binding to anti-apoptotic proteins via the BH3 domains of Bcl-2-family-member proteins. GX15–070MS is a small-molecule antagonist of the BH3-binding groove of the Bcl-2 family of proteins that can inhibit the interactions of Bcl-2 with proapoptotic molecules. We examined the activity of GX15–070MS on CLL cells in vitro and in vivo in a phase I/II clinical study initiated at our institution for patients with intermediate-risk or high-risk disease refractory to alkylating drugs, fludarabine-based regimens, and, in some cases also Alemtuzumab. Patients were treated with the initial escalating doses of 3.5 and 7 mg/m2. Administration of GX15–070 has been well tolerated and patients have not experienced any Grade 3 or Grade 4 toxicity. We have evaluated in vitro and in vivo the pro-apoptotic activity of GX15–070MS. GX15–070MS induced apoptosis in CLL-B cells in a time and dose-dependent manner with an IC50=10nM at 48 hours in culture. GX15–070MS induced apoptosis in CLL B cells independent of IgVH gene mutational status or ZAP-70 expression. In addition, we have analyzed the effect of this compound based on co-immunoprecipitations and Bcl-2/Mcl-1 mitochondrial displacement assays using video-confocal microscopy. These results indicate that GX15–070MS has activity inhibiting Bcl-2 family member proteins and inducing apoptosis in CLL B cells both in vitro and in vivo at dose ranges that are substantially below those estimated to induce toxicity in preclinical animal models. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gemin X