SM09419 / Biosplice Therap - LARVOL DELTA

The CLK/DYRK inhibitor SM09419 shows potent efficacy across a broad panel of pediatric preclinical xenograft models - A report from the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) (AACR 2025) - P1 | "SM09419 exhibited promising activity in preclinical models of TP53- and FLT3-mutated acute myeloid leukemia, and its analog cirtuvivint (SM08502) exhibited broad preclinical activity and evidence of therapeutic benefit in solid tumors. SM09419 exhibited broad antitumor activity across several pediatric cancers (e.g., ALL and NB), with activity also observed for ES and HB. Lower activity was seen in the RMS and OS models. The promising results support further evaluation of CLK/DYRK as therapeutic targets."

Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • CNS Tumor • Ewing Sarcoma • Hematological Malignancies • Hepatoblastoma • Leukemia • Neuroblastoma • Oncology • Osteosarcoma • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor • FLT3 • TP53

Cirtuvivint inhibits Ewing sarcoma (ES) growth by suppressing EWS-FLI-1 expression and inducing alternate EWS-FLI1 splice variants (AACR 2025) - "Treatment of ES cells (A673, CHP100, and MHH ES1) with increasing concentrations of cirtuvivint, as well as its analog SM09419, significantly reduced cell viability (LD50 ~250 nM) both in vitro and in vivo, This treatment suppressed EWS-FLI-1 expression and generated multiple alternative EWS-FLI-1 variants within 4-6 hours, marked by the loss of whole exons. Mechanistic studies showed reduced β-catenin and c-myc expression, however, siRNA experiments targeting these genes did not affect cell growth. To investigate the role of these alternative EWS-FLI1 splice variants, transcripts generated by cirtuvivint treatment were cloned, sequenced, and inserted into eukaryotic expression vectors, including a Tet-inducible system and vectors for cell-free protein expression."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CDK1 • CTNNB1 • EWSR1 • FLI1 • MYC

ALTERNATIVE SPLICING (AS) REGULATION AS A NOVEL THERAPEUTIC TARGET IN SOFT-TISSUE SARCOMA (STS) (CTOS 2023) - "Objective: There is an urgent clinical need to identify novel treatments for advanced STS, since all the clinical trials testing chemotherapy combinations have failed to improve survival compared to doxorubicin (dox) alone... A panel of 9 STS cell lines, including leiomyosarcoma (CP0024, IEC005, AA and SK-UT-1), liposarcoma (93T449), synovial sarcoma (MCP037) and UPS (MCP016, MCP021 and MCP025) were used to analyse the effect of SM09419 (provided by Biosplice) or PRI-724 (Wnt/β-catenin inhibitor) treatment on cell viability (MTS assays)... The effects of pan CLK/DYRK inhibition on growth and survival of STS cancer cell lines and PDX models, indicate that can STS can potentially be therapeutically addressed with these AS-modulators. The combination of SM09419 with dox was active in STS preclinical models known for their resilience toward treatment. Based on these results, the exploration of such combinations in clinical trials is warranted."

Leiomyosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Therapeutic modulation of RNA splicing to combat malignant rhabdoid tumors (EACR 2023) - "ConclusionOur results suggest that targeting RNA splicing may be a promising approach for treatment of therapy-refractory MRT. Further pre-clinical in vivo studies are warranted to fully establish a rationale for clinical evaluation of SM09419 in MRT patients."

Oncology • Pediatrics • Rhabdoid Tumor • Sarcoma • CASP3 • CASP7 • SMARCB1 • TCF7

Alternative splicing (AS) regulation as a novel therapeutic target in soft-tissue sarcoma (STS). (ASCO 2023) - "Background: There is an urgent clinical need to identify novel treatments for advanced STS, since all the clinical trials testing chemotherapy combinations have failed to improve survival compared to doxorubicin (dox) alone... A panel of 9 STS cell lines, including LMS (CP0024, IEC005, AA, SK-UT-1), LPS (93T449), synovial sarcoma (MCP037) and UPS (MCP016, MCP021, MCP025) were used to analyse the effect of SM09419 (provided by Biosplice) or PRI-724 (Wnt/β-catenin inhibitor) on cell viability (MTS assays)... The effects of pan CLK/DYRK inhibition on growth and survival of STS cancer cell lines and PDX models, indicate that can STS may be therapeutically addressed with these AS-modulators. The combination of SM09419 with dox was active in STS preclinical models known for their resilience toward treatment. Based on these results, the exploration of such combinations in clinical trials is warranted."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Modulation of RNA Splicing Enhances Response to BCL2 Inhibition in Acute Myeloid Leukemia (ASH 2021) - "We therefore utilized a series of selective pan-CLK/DYRK1A inhibitors, including SM09419 and SM08502, that potently suppress SR protein phosphorylation. Therapeutically, pharmacologic inhibition of SR protein function via inhibiting CLK/DYRK1A-mediated phosphorylation of splicing factors is an effective strategy used in combination with venetoclax or to overcome venetoclax resistance. Overall, our findings underscore the central importance of RNA splicing in drug response and provides a therapeutic rationale for modulating RNA splicing to enhance current AML therapies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2A1 • CDK1 • RBM10 • TP53