SIK1 inhibitors(salt inducible kinase 1 inhibitors), SIK2 inhibitors(Serine/threonine-protein kinase SIK2 inhibitors), SIK3 inhibitors(SIK family kinase 3 inhibitors)

Therapeutic Areas

Endocrinology and Metabolic DiseaseSkin and Musculoskeletal DiseasesOther Diseases

Active Indication

OsteoporosisInflammation

Inactive Indication-

Originator Organization

Galapagos SA

Active Organization

UMass Chan Medical School

Harvard Medical SchoolGalapagos SA

+ [1]

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC23H22N6O3

InChIKeyVOYZWDQJVPQGCO-UHFFFAOYSA-N

CAS Registry2760404-50-8

100 Clinical Results associated with SK-124

100 Translational Medicine associated with SK-124

100 Patents (Medical) associated with SK-124

Literatures (Medical) associated with SK-124

13 Dec 2022·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice

Q1 · CROSS-FIELD

Article

Author: Lanske, Beate ; Sato, Tadatoshi ; Bouxsein, Mary L. ; Andrade, Christian D. Castro ; Yoon, Sung-Hee ; Wein, Marc N. ; Greenlee, William J. ; Kulp, John ; Zhao, Yingshe ; Mitlak, Bruce ; Viswanathan, Usha ; Brooks, Daniel J. ; Demay, Marie B. ; Weber, Patricia C.

Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124.

01 Nov 2022·Journal of Biological Chemistry

Rapid genomic changes by mineralotropic hormones and kinase SIK inhibition drive coordinated renal Cyp27b1 and Cyp24a1 expression via CREB modules

Article

Author: Wein, Marc N ; Benkusky, Nancy A ; Lee, Seong Min ; Meyer, Mark B ; Yoon, Sung-Hee ; Pike, J Wesley ; Mannstadt, Michael

Vitamin D metabolism centers on kidney regulation of Cyp27b1 by mineralotropic hormones, including induction by parathyroid hormone (PTH), suppression by fibroblast growth factor 23 (FGF23) and 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and reciprocal regulations for Cyp24a1. This coordinated genomic regulation results in production of endocrine 1,25(OH)₂D₃, which, together with PTH and FGF23, controls mineral homeostasis. However, how these events are coordinated is unclear. Here, using in vivo chromatin immunoprecipitation sequencing in mouse kidney, we demonstrate that PTH activation rapidly induces increased recruitment of phosphorylated (p-133) CREB (pCREB) and its coactivators, CBP (CREB-binding protein) and CRTC2 (CREB-regulated transcription coactivator 2), to previously defined kidney-specific M1 and M21 enhancers near the Cyp27b1 gene. At distal enhancers of the Cyp24a1 gene, PTH suppression dismisses CBP with only minor changes in pCREB and CRTC2 occupancy, all of which correlate with decreased genomic activity and reduced transcripts. Treatment of mice with salt-inducible kinase inhibitors (YKL-05-099 and SK-124) yields rapid genomic recruitment of CRTC2 to Cyp27b1, limited interaction of CBP, and a transcriptional response for both Cyp27b1 and Cyp24a1 that mirrors the actions of PTH. Surprisingly, we find that 1,25(OH)₂D₃ suppression increases the occupancy of CRTC2 in the M1 enhancer, a novel observation for CRTC2 and 1,25(OH)₂D₃ action. Suppressive actions of 1,25(OH)₂D₃ and FGF23 at the Cyp27b1 gene are associated with reduced CBP recruitment at these CREB-module enhancers that disrupts full PTH induction. Our findings show that CRTC2 contributes to transcription of both Cyp27b1 and Cyp24a1, demonstrate salt-inducible kinase inhibition as a key modulator of vitamin D metabolism, and provide molecular insight into the coordinated mechanistic actions of PTH, FGF23, and 1,25(OH)₂D₃ in the kidney that regulate mineral homeostasis.

100 Deals associated with SK-124

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoporosis	Preclinical	US	Harvard Medical School	06 Dec 2022
Osteoporosis	Preclinical	US	UMass Chan Medical School	06 Dec 2022
Osteoporosis	Preclinical	US	Radius Health, Inc.	06 Dec 2022
Inflammation	Discovery	FR	Galapagos SA	26 Dec 2023

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