Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma

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.

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

“…Ibrutinib can promote the mutation of cysteine 481 of BTK required for irreversible binding of ibrutinib to BTK. We previously demonstrated that SRX3262 and SRX3305 exhibited cytotoxic effects in malignant B-cells harboring the BTK-C481S mutation [ 37 , 38 ]. In addition to mutations in drug-targeting proteins, several non-genetic mechanisms rendering CLL cells resistant to ibrutinib have been described and usually manifest as upregulation of alternative survival signaling pathways, such as the PI3K/AKT/ERK [ 67 ].…”

“…PI3K and BTK inhibitors have also been combined to intercept constitutive BCR pathway signaling at multiple points [ 77 ]. While combination approaches have shown promising preclinical efficacy, the increased risk of toxicity when combining multiple small-molecule-targeted agents remains an evident concern [ 38 , 78 ]. Individual drugs used to inhibit BTK, PI3K, and BET proteins each have unique side-effect profiles, and as such, additive side-effects from simultaneous inhibition of these pathways may occur.…”

“…We recently introduced thienopyranone (TP) scaffold-based chemotypes [ 36 ] for the combinatorial inhibition of BTK, PI3K-AKT, and BRD4-MYC in a single compound (i.e., SRX3262 and SRX3305) and demonstrate impressive preclinical activity in mantle cell lymphoma (MCL) [ 37 , 38 ]. BTK/PI3K/BRD4 triple-inhibitors present a potential solution to the toxicity that often plagues combination therapeutic strategies that are necessary to overcome CLL progression and drug resistance.…”

A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia

“…Ibrutinib can promote mutation of cysteine 481 of BTK, required for irreversible binding of ibrutinib to BTK. We previously demonstrated that SRX3262 and SRX3305 exhibited cytotoxic effects in malignant B-cells harboring the BTK-C481S mutation [37,38]. Besides mutations in drug-targeting proteins, several non-genetic mechanisms rendering CLL cells resistant to ibrutinib have been described and usually manifest as upregulation of alternative survival signaling pathways, such as the PI3K/AKT/ERK [57].…”

“…PI3K and BTK inhibitors have also been combined to intercept constitutive BCR pathway signaling at multiple points [67]. While these approaches have shown promising preclinical efficacy, the increased risk of toxicity when combining multiple small molecule targeted agents remains an evident concern [38,68]. Herein lies the profound benefit of a single multi-target agent with the capability to simultaneously disrupt three key CLL pathogenic entities.…”