Abstract A085: OBP-004, a novel small-molecule dual inhibitor of CDK9/13, reduces bone, brain, lung and lymph node metastases in vivo, with highest potency on bone metastases
Bibliographic record
Abstract
Abstract Cyclin-dependent kinases (CDKs) are promising targets in metastatic cancers. OBP-004 is a novel highly potent and selective small-molecule dual inhibitor of CDK9/13. It has a half-life of 17-20 hours and high tissue biodistribution in brain, lung, spleen and kidneys, and with no observed safety issues. Metastases are the main cause of cancer-related deaths. Advanced stage triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) patients have a high incidence of bone metastases that are mostly unresponsive to current treatments. In this study, we demonstrate preclinical efficacy of OBP-004 on metastatic tumor burden, and more specifically on TNBC and CRPC bone metastases using sophisticated preclinical models. For studying efficacy on multiple metastases, female NMRI nude mice were inoculated intravenously with luciferase-labelled MV4-11 human acute myeloid leukemia cells and randomized to treatment groups at day 15 based on body weight and bioluminescence imaging (BLI) signal. OBP-004 was given orally at a dose of 1.0 mg/kg three times a week (3-day on, 4-day off) starting at day 15 after the cancer cell inoculation. Tumor burden was monitored by BLI and the study was terminated at day 32. To model bone metastases in vivo, female BALB/c or castrated male C57BL mice were inoculated intratibially with luciferase-labelled 4T1 mouse TNBC or RM-1 mouse CRPC cells, respectively, and randomized to treatment groups at day 4 based on body weight and BLI signal. OBP-004 was given orally starting at day 4 after the cancer cell inoculation at a dose of 0.8 mg/kg three times a week (Mon/Wed/Fri) in the TNBC model and 0.6 mg/kg daily in the CRPC model. The TNBC study was terminated at day 21, and the CRPC study at day 28 after the cancer cell inoculation. During the study, tumor growth was monitored by BLI, cancer-induced bone changes by X-ray radiography, and bone pain by mechanical allodynia using Von Frey filaments. The initial 1.0 mg/kg dosing (3-day on, 4-day off) of OBP-004 in the MV4-11 study resulted in slight decrease of body weight without any clinical signs. The optimized dosing schedules, either with 0.8 mg/kg (Mon/Wed/Fri) or 0.6 mg/kg daily in the TNBC and CRPC studies, was well tolerated with no changes in body weight. In the MV4-11 model, OBP-004 showed strong decrease of brain, lung and lymph node metastases, and almost complete (>99.9%) abolishment of bone metastases. In both the TNBC and CRPC models, OBP-004 showed strong inhibition of tumor growth in bone, decreased cancer-induced bone loss and decreased bone pain. We conclude that OBP-004, a highly potent and selective dual inhibitor of CDK9/CDK13, is a promising preclinical drug candidate especially for the treatment of bone metastatic TNBC and CRPC. These results indicate that OBP-004 affects both tumor growth and cancer-induced bone changes, and the observed decrease in bone pain indicates potential for increasing the quality of life of bone metastatic patients. Citation Format: Tiina E. Kähkönen, Gergana Galabova, Jie Wen, Ru Yang, Michael Thormann, Jussi Halleen. OBP-004, a novel small-molecule dual inhibitor of CDK9/13, reduces bone, brain, lung and lymph node metastases in vivo, with highest potency on bone metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A085.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".