SF2523 / SignalRx, ADYA Consulting - LARVOL DELTA

SF2523, a dual PI3K-BRD4 inhibitor, enhances KRAS (G12C) or EGFR (exon 19/21) mutant targeted inhibitors in non-small-cell lung cancer (NSCLC) (AACR 2025) - "Sotorasib and Adagrasib are a second line therapy for KRAS G12C mutant NSCLC...SF2523 IC50 in EGFR mutated NSCLC cells ranged from 90-230nM, while in KRAS mutated NSCLC cells ranged from 144-217nM versus Buparlisib plus JQ1 in the μM range...In contrast, combinations of SF2523 plus Nindetinib (VEGFR inhibitor) or Rapamycin (mTOR inhibitor) were additive in potency with EGFR and KRAS mutant NSCLC cell lines...In a SCID H2030 KRAS G12C mouse xenograft model, SF2523 at a dose of 150 mg/kg was well tolerated without weight loss with tumor growth inhibition of >60% at 6 weeks. In conclusion, our results demonstrate SF2523 is active alone and is synergistic with Osimertinib or Sotorasib in inhibiting EGFR or KRAS mutant NSCLC cell lines and is active as a single agent in a KRAS G12C mutated H2030 CDX NSCLC mouse model."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKT1 • BRD4 • EGFR • KRAS • MYC • PIK3CA • PTEN

LC-MS/MS method for the quantitation of a dual PI3K/BRD4 inhibitor SF2523 in mouse plasma: application to plasma protein binding and metabolism studies. (PubMed, Biomed Chromatogr) - "Metabolites identification included analysis of retention behaviors, molecular weight changes and MS/MS fragment patterns of SF2523 and the metabolites. This newly developed and validated method allows the rapid and easy determination of the SF2523 concentration with high sensitivity in low sample volume and can be applied to future pre-clinical studies."

Journal • Preclinical • BRD4

The Effectiveness and Mechanical Properties of Chemotherapy-Impregnated Cement in Ewing Sarcoma. (PubMed, J Orthop Res) - "Chemotherapeutic agents including doxorubicin, cisplatin, etoposide, and SF2523 were mixed with bone cement. Additionally, there was a synergistic effectiveness of the CIC noted when multiple antineoplastic agents were combined. Three-point-bending tests did not reveal substantial reductions in tolerated maximum bending load and maximal displacement at maximal bending load between CIC and RBC."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

Targeting BRD4 and PI3K signaling pathways for the treatment of medulloblastoma. (PubMed, J Control Release) - "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."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • BRD2 • BRD4 • MYC

Promoting autophagy to mitigate coronavirus disease pathology in the elderly. (PubMed, Clin Transl Discov) - "Furthermore, across varying dosages, SF2523 was shown to have a synergistic effect with remdesivir or MU-UNMC. Consequently, we believe that SF2523, alone or with other anti-virals, is a promising potential therapeutic for preventing SARS-CoV-2-related mortalities."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Combining antiviral drugs with BET inhibitors is beneficial in combatting SARS-CoV-2 infection. (PubMed, Clin Transl Discov) - "We recently showed that SF2523, a dual activity small molecule that inhibits PI3K and BRD4, acts synergistically with the antiviral drugs remdesivir and MU-UNMC-2. Our findings suggest that the mTOR pathways are necessary for SARS-CoV-2 pathogenesis in human cells and targeting PI3K/BET (bromodomain and extra-terminal domain proteins) alone or combined with antiviral therapies is beneficial in mitigating SARS-CoV-2 and its variants of concern (VOCs)."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • BRD4

Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia. (PubMed, Front Oncol) - "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."

IO biomarker • Journal • Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • CASP3 • CASP7 • CXCR4 • ITGA4 • MYC • PARP1 • PIK3CD

The Novel Multitarget Small-Molecule Inhibitor SRX3177 Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma (ASH 2021) - "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."

IO biomarker • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • ATM • BCL2 • BRD4 • CCND1 • CDKN2A • MYC • PIK3CA • PIK3CD • TP53

Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma. (PubMed, Biomaterials) - "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."

Journal • Brain Cancer • Hepatology • Medulloblastoma • Oncology • Solid Tumor • BAX • BRD4 • CCND1 • MYC • MYCN

Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma. (PubMed, J Pediatr Hematol Oncol) - "In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth. (PubMed, Oncotarget) - "...Remarkably, SF2523 was more efficient than Wortmannin (the PI3K inhibitor) and JQ1 (the BRD4 specific inhibitor) in killing RCC cells. In vivo, SF2523 administration at well-tolerated doses suppressed 786-O xenograft tumor growth in severe combined immunodeficient (SCID) mice. Together, our results suggest that concurrent blockage of BRD4 and PI3K-AKT signalings by SF2523 efficiently inhibits RCC cell growth in vitro and in vivo."

Journal • Biosimilar • Gene Therapies • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo. (PubMed, Biochem Biophys Res Commun) - "BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and AKT-S6K1 activation were inhibited in SF2523-treated tumors. Together, dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo."

Journal • Biosimilar • Gene Therapies • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

SF2523: Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer. (PubMed, Mol Cancer Ther) - "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."

Journal • Oncology • Solid Tumor

SF2523 inhibits human chondrosarcoma cell growth in vitro and in vivo. (PubMed, Biochem Biophys Res Commun) - "It was more efficient in killing chondrosarcoma cells than other established PI3K-Akt-mTOR and BRD4 inhibitors, including JQ1, perifosine and OSI-027. Akt-mTOR inhibition as well as Bcl-2 and c-Myc downregulation were detected in SF2523-treated SW1353 tumor tissues. In conclusion, targeting PI3K-Akt-mTOR and BRD4 by SF2523 potently inhibited chondrosarcoma cell growth in vitro and in vivo."

Journal • Preclinical