Abstract 7041: 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)

Abstract Introduction: SM09419 is an experimental small-molecule pan-inhibitor targeting CLK and DYRK kinases, which play a key role in RNA splicing and other oncogenic processes. 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. Cirtuvivint is in clinical trials in adults with AML (NCT06484062) and sarcomas (SELNET-7-2/EuCT#: 2024-511987-10-00). To evaluate the role of CLK and DYRK kinase inhibition in pediatric cancers, SM09419 was tested against panels of pediatric solid tumor and leukemia patient-derived xenografts (PDXs). Methods: SM09419 was provided by Biosplice Therapeutics and administered orally at 25 mg/kg daily for 5 days per week x 3 weeks for the acute lymphoblastic leukemia (ALL), neuroblastoma (NB), sarcoma (SARC) and hepatoblastoma (HB) models. Tolerability was assessed in groups of 3 non-tumor bearing immune-deficient mice (NSG, CB17 SCID) at 100%, 75% and 50% of the recommended dose of 25 mg/kg. For efficacy testing, a single mouse trial (SMT) design (one vehicle control, one drug treated mouse per PDX) was used for ALL (n=30 PDXs), NB (n=14), HB (n=7), Ewing sarcoma (ES, n=8), rhabdomyosarcoma (RMS, n=5), Wilms tumor (WT, n=2) and malignant rhabdoid tumors (MRT, n=3). For the osteosarcoma (OS, n=6) models a conventional study design of 10 mice per group (vehicle or drug) was employed. Standard PIVOT methods were used to assess event-free survival (EFS T/C = ratio of median EFS for treated versus control animals). Stringent objective response measures (ORMs) modeled after the clinical setting were also used to evaluate activity (Houghton et al., Pediatr Blood Cancer, 2007). Results: SM09419 was well tolerated at all dose levels with <20% weight loss observed, irrespective of the mouse strain. SM09419 showed objective responses (ORMs of partial response, PR; complete response, CR; maintained CR, MCR) against 20/28 evaluable ALL, 6/14 NB, 2/7 HB, 2/8 ES, 0/2 WT, 0/5 RMS, 0/3 MRT PDXs tested. EFS T/C values ranged from 0.4-9.3 (ALL), 1.2-7.0 (NB), 0.64-2.7 (HB), 1.0-5.9 (ES), 0.37-0.81 (WT), 0.65-1.8 (RMS) and 1.7-2.0 (MRT). No objective responses were observed in the 6 OS models, with 4 showing growth delay (EFS T/C >2). Conclusions: 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. Future research directions for these cancers include identifying biomarkers that predict sensitivity to CLK/DYRK inhibition as well as efforts to identify effective combinations with targeted and/or standard-of-care drugs. Citation Format: Richard B. Lock, Raushan Kurmasheva, Kathryn Evans, David Groff, Ben Watts, Kateryna Krytska, Christopher M. Smith, Faith N. Key, Daniella Cofini, Miguel Agoncillo, Steven Neuhauser, Timothy M. Stearns, Emily L. Jocoy, Jee Young Kwon, Jeffrey H. Chuang, Beverly A. Teicher, Richard Gorlick, Yael P. Mossé, John M. Maris, Peter J. Houghton, Carol J. Bult, Malcolm A. Smith. 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) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7041.