abt-199 and Waldenstrom-Macroglobulinemia

BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.. We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.. Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were. Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Female; Humans; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins c-bcl-2; Receptors, CXCR4; Sulfonamides; Time Factors; United States; Waldenstrom Macroglobulinemia

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Waldenstrom Macroglobulinemia

In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual-site'-binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co-binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed - Venetoclax increased the binding affinity of JQ1 by 11.5 %, while JQ1 boosted the binding affinity of Venetoclax by 16.3 % when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.

Topics: Antineoplastic Agents; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Triazoles; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lymphoma, B-Cell; Molecular Targeted Therapy; Nerve Tissue Proteins; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Receptors, Cell Surface; Sulfonamides; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Membrane Proteins; Piperidines; Proto-Oncogene Proteins; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, CXCR4; Sulfonamides; Waldenstrom Macroglobulinemia