SF2523

MDP5 showed higher potency in DAOY cells (IC 5.5 μM) compared to SF2523 (IC 12.6 μM), and its IC values in HD-MB03 cells were like SF2523. Treatment of MB cells with MDP5 significantly decreased colony formation, increased apoptosis, and halted cell cycle progression. Further, MDP5 was well tolerated in NSG mice bearing either xenograft or orthotopic MB tumors at the dose of 20 mg/kg, and significantly reduced tumor growth and prolonged animal survival.

Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.

Moreover, systemic administration of COG-133-NPs loaded with MDB5 and SF2523 resulted in decreased tumor burden compared to non-targeted drug-loaded NPs, without any hepatic toxicity. In conclusion, our nanomedicine of MDB5 and SF2523 offers a novel therapeutic strategy to treat chemoresistant MB.

Although there is no defined standard of care for MCL treatment, some combination of chemo-immunotherapy and rituximab maintenance with or without autologous stem cell transplantation is generally employed depending on the age and fitness of the patient...Further, we show that SRX3177 is more potent to tumor cells than the individual PI3K (BKM120), BTK (Ibrutinib), BRD4 (JQ1), and CDK4/6 (palbociclib) inhibitors, and dual PI3K/BRD4 inhibitor SF2523 (backbone for SRX3177) in JeKo-1 cells...Hence, the triple inhibitor SRX3177 has superior potency to ibrutinib in MCL cell lines and succeeds in overcoming ibrutinib-resistance at nanomolar doses. Taken together, our data supports the development of SRX3177 as a novel therapeutic agent for treatment of MCL.

Pharmacological inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous murine cancer models; reduces infiltration of myeloid-derived suppressor cells (MDSCs); blocks polarization of immunosuppressive macrophages; restores CD8+ T-cell activity and stimulates anti-tumor immune responses. Finally, our results suggest that BRD4 regulates the immunosuppressive myeloid tumor microenvironment and BET inhibitors and dual PI3K/BRD4 inhibitors are therapeutic strategies for cancers driven by the macrophage-dependent immunosuppressive TME.