Abstract
Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma characterized by poor prognosis. The complexity of MCL pathogenesis arises from aberrant activities of diverse signaling pathways, including BTK, PI3K–AKT–mTOR and MYC-BRD4. Here, we report that MCL-related signaling pathways can be altered by a single small molecule inhibitor, SRX3305. Binding and kinase activities along with resonance changes in NMR experiments reveal that SRX3305 targets both bromodomains of BRD4 and is highly potent in inhibition of the PI3K isoforms α, γ and δ, as well as BTK and the drug-resistant BTK mutant. Preclinical investigations herein reveal that SRX3305 perturbs the cell cycle, promotes apoptosis in MCL cell lines and shows dose dependent anti-proliferative activity in both MCL and drug-resistant MCL cells. Our findings underscore the effectiveness of novel multi-action small molecule inhibitors for potential treatment of MCL.
Highlights
Mantle cell lymphoma (MCL) is a mature B cell malignancy with characteristic t(11;14)(q13;q32) translocation juxtaposing IGH and CCND1 gene loci [1]
SRX3305 binds to BRD4 and inhibits Bruton’s tyrosine kinase (BTK) and Phosphatidylinositol-3 kinase (PI3K) In effort to develop small molecule agents which act against MCL, we designed a series of thienopyranone (TP)-based compounds with the ability to concomitantly bind bromodomains (BDs) of BRD4, the catalytic domain of BTK, and the catalytic domain of PI3K
Among the new set of inhibitors, SRX3305 showed a substantial increase in potency for all three targets, BTK, PI3K and BRD4 compared to SRX3262 (Fig. 1a)
Summary
Mantle cell lymphoma (MCL) is a mature B cell malignancy with characteristic t(11;14)(q13;q32) translocation juxtaposing IGH and CCND1 gene loci [1]. This translocation leads to overexpression of cyclin D1 and dysregulation of the cell cycle at the G1/S phase transition. While treatment with combination chemotherapeutic regimens is initially effective, most patients relapse with a median survival of only 2.5 – 5 years [2, 3]. Despite the high overall response rate seen in relapsed/ refractory (R/R) MCL patients treated with Ibrutinib (68%), only 21% of patients reached a complete response with a median progression free survival of ~14 months [6]. Resistance to Ibrutinib is common, and there are few approved therapies capable of improving MCL patient outcome to an extent, making the post-FDA approved R/R MCL treatment setting an unmet clinical need [11]
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