A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia

• Published in: International journal of molecular sciences Vol. 23; no. 12; p. 6712
• Main Authors: Smith, Audrey L, Eiken, Alexandria P, Skupa, Sydney A, Moore, Dalia Y, Umeta, Lelisse T, Smith, Lynette M, Lyden, Elizabeth R, D'Angelo, Christopher R, Kallam, Avyakta, Vose, Julie M, Kutateladze, Tatiana G, El-Gamal, Dalia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-06-2022; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Apoptosis; B-cell receptor; B-cell receptor signaling; BET/BRD4 proteins; BTK; Cancer; Cell cycle; Cell Cycle Proteins - pharmacology; Cell growth; Cell proliferation; Chemical compounds; Chemokines; Chronic lymphocytic leukemia; Disease; Drug dosages; Drug resistance; Epigenetics; Gene expression; Homing behavior; Humans; Inhibitors; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytes B; Lymphoma; Microenvironments; Mutation; Nuclear Proteins; Pathogenesis; Pharmacology; Phosphatidylinositol 3-Kinases; Phosphorylation; PI3K; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Receptors, Antigen, B-Cell - metabolism; Signal transduction; Survival; targeted small molecule inhibitor; Toxicity; Transcription Factors; Tumor Microenvironment; Tumors; BTK; chronic lymphocytic leukemia; PI3K; BET/BRD4 proteins; B-cell receptor signaling; targeted small molecule inhibitor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23126712

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.