Nimbus Therapeutics Announces First-in-Human Dosing of NDI-225673, an Investigational Selective SIK2 Inhibitor for Immune-Mediated Inflammatory Diseases
— First-in-class oral inhibitor designed to selectively target SIK2 to suppress inflammation and promote resolution
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Nimbus Therapeutics, LLC (“Nimbus Therapeutics” or “Nimbus”), a computational drug discovery company developing breakthrough small molecule medicines through advanced structure-based design and AI-enabled chemistry, today announced that the first subjects have been dosed in its Phase 1 clinical trial of NDI-225673, an investigational, oral, highly selective inhibitor of salt-inducible kinase 2 (SIK2) for the potential treatment of immune-mediated inflammatory diseases. The Phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of NDI-225673 in healthy volunteers.
Salt-inducible kinases (SIKs) comprise three closely related isoforms (SIK1, SIK2, and SIK3). SIK2 regulates transcriptional programs involved in inflammatory responses and their resolution, particularly in myeloid cells such as macrophages. In preclinical studies, selective SIK2 inhibition suppressed a broad set of key inflammatory drivers, including TNFα, IL-6, IL-23, and IL-1β, many of which are validated targets of approved biologics for inflammatory diseases. Additionally, selective SIK2 inhibition increased IL-10 and tissue-repair mediators, including amphiregulin (AREG) and thrombospondin-1 (THBS1), supporting its potential to combine broad anti-inflammatory activity with resolution and tissue repair.
In preclinical studies, NDI-225673 demonstrated potent nanomolar cellular activity and high selectivity for SIK2, supporting its potential to minimize potential liabilities associated with inhibition of other SIK isoforms.
“Many patients with immune-mediated inflammatory diseases, such as ulcerative colitis and rheumatoid arthritis, do not reach durable remission on current therapies,” said Peter Tummino, Ph.D., President of Research and Development at Nimbus. “Our goal with selective SIK2 inhibition is to go beyond suppressing individual inflammatory cytokines by engaging biological pathways that regulate inflammation and tissue repair. NDI-225673 represents years of research to achieve a high degree of SIK isoform selectivity, and this Phase 1 study gives us the opportunity to begin testing the SIK2 hypothesis directly in humans.”
About NDI-225673
NDI-225673 is an investigational, oral, highly selective small molecule inhibitor of SIK2, designed using Nimbus’ proprietary high-resolution crystal structures to target SIK2 while sparing SIK1 and SIK3. SIK1 inhibition has been associated with cardiovascular risk, and SIK3 loss of function with skeletal and fertility-related defects. These findings suggest that selectively targeting SIK2 may offer a more favorable therapeutic profile in inflammatory disease.
In preclinical studies, selective SIK2 inhibition with NDI-225673 broadly suppressed multiple pro-inflammatory cytokines while inducing the anti-inflammatory cytokine IL-10 and tissue-repair mediators in human macrophages. In mouse models of colitis, SIK2 inhibition reduced disease activity and improved markers of gut barrier integrity, including mucin and occludin, and in a mouse arthritis model SIK2 inhibition reduced joint inflammation. By combining anti-inflammatory activity with resolution and tissue repair, NDI-225673 has the potential to address immune-mediated inflammatory diseases in gastroenterology, rheumatology, and dermatology.
About Nimbus Therapeutics
Nimbus Therapeutics is a leader in computational drug discovery, developing breakthrough small molecule medicines against well-validated, difficult-to-drug targets. Nimbus brings together deep expertise in structure-based drug discovery and advanced computational chemistry with AI- and machine learning-enabled predictive modeling in a proven drug discovery engine designed to create differentiated medicines across multiple therapeutic areas.
Nimbus’ pipeline includes NDI-219216, a Werner syndrome helicase (WRN) inhibitor in Phase 1/2 clinical development for microsatellite instability-high (MSI-H) solid tumors; NDI-225673, a salt-inducible kinase 2 (SIK2) inhibitor in Phase 1 clinical development for inflammatory and autoimmune diseases; and multiple preclinical programs across oncology, immunology, and metabolic diseases. Nimbus is headquartered in Boston, Massachusetts. To learn more, visit www.nimbustx.com.
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