ARN-3236 / Arrien - LARVOL DELTA

Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair. (PubMed, MedComm (2020)) - "Importantly, ARN-3236, a SIK2 inhibitor, markedly sensitized CRC cells to radiation both in vivo and in vitro, providing a potential strategy to overcome radioresistance. In summary, our findings reveal a novel mechanism by which SIK2 contributes to the radioresistance of CRC, proposing SIK2 as a potential therapeutic target with its inhibitor significantly enhancing CRC radiotherapy efficacy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HRD • RAD51

Computational insights into marine natural products as potential antidiabetic agents targeting the SIK2 protein kinase domain. (PubMed, SAR QSAR Environ Res) - "Molecular dynamics simulations (MDS) revealed stronger predicted binding affinity for these compounds compared to ARN-3236, a known SIK2 inhibitor. Principal component (PC)-based free energy landscape (FEL) analysis further supported the stable binding of these compounds to SIK2. These computational findings highlight the potential of these leads as novel SIK2 inhibitors, warranting future in vitro and in vivo validation."

Journal • Diabetes • Metabolic Disorders

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers. (PubMed, J Clin Invest) - "We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • DRD • FANCD2 • HDAC4 • MEF2D • XRCC4

Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice. (PubMed, BMC Pulm Med) - "In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TGFB1

SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. (PubMed, Oncogene) - "ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and β-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/β-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/β-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs."

Journal • Breast Cancer • Oncology • Solid Tumor • IDH1

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway. (PubMed, Front Pharmacol) - "Moreover, we demonstrated that the hippocampal CRTC1-CREB-BDNF pathway mediated the antidepressant-like efficacy of ARN-3236. Collectively, ARN-3236 possesses strong protecting effects against chronic stress, and could be a novel antidepressant beyond monoaminergic drugs."

Journal • CNS Disorders • Depression • Gene Therapies • Psychiatry • BDNF

SIK2 inhibitors regulate DNA repair pathway and sensitize ovarian cancer to PARP1 inhibitors (AACR 2018) - "Here we ask whether inhibition of SIK2 can enhance HDAC class-IIa inhibition of MEF activity, decrease DNA repair and enhance sensitivity to the PARP inhibitor Olaparib in ovarian cancer cells.Treatment with SIK2 inhibitors (ARN3236 or ARN3261) enhanced sensitivity to Olaparib in each of 8 ovarian cancer cell lines without BRCA1/2 mutations (OC316, OVCAR8, IGROV1, A2780, HCC5030, HCC5032, SKOv3 and OVCAR5) and significantly reduced the IC50 of Olaparib in two PARP inhibitor-resistant ovarian cancer cell lines (A2780CP-R and UWB1-289-10R). DNA damage, judged by rH2AX expression was enhanced by SIK2 inhibition. These observations not only provide new insights into the transcriptional regulation of DNA repair gene expression, but also have important implications for enhancing sensitivity of high grade serous ovarian cancers to PARP inhibition, with or without BRCA1 or BRCA2 germline mutations."

BRCA Biomarker • PARP Biomarker • Ovarian Cancer

[VIRTUAL] Novel SIK2 inhibitors sensitize ovarian and breast cancer to PARP inhibitors (AACR-II 2020) - "SIK2 inhibition enhances paclitaxel sensitivity in both cancer types. We have demonstrated that olaparib-induced-growth inhibition was significantly enhanced by concurrent treatment with either ARN3236 or ARN3261 in each of 12 ovarian and breast cancer cell lines tested, but not in 3 non-tumorigenic cell lines...Together, our data argue that the combination of a SIK2 inhibitor and a PARP inhibitor has the potential to increase the magnitude and duration of PARP inhibitor activity with tolerable toxicity. Use of a SIK2 inhibitor in combination with a PARP inhibitor provides a novel therapeutic strategy for ovarian and triple negative breast cancers with or without BRCA gene mutation."

Breast Cancer • Gynecologic Cancers • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • AMPK • BRCA • BRCA1 • BRCA2 • FANCD2 • HRD • XRCC4

SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. (PubMed, J Leukoc Biol) - "...With the use of 2 structurally unrelated, selective salt-inducible kinase inhibitors, HG-9-91-01 and ARN-3236, we showed that salt-inducible kinase inhibition significantly decreased proinflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-12p40) and increased IL-10 secretion by human myeloid cells stimulated with TLR2 and-4 agonists...More importantly, we showed for the first time that salt-inducible kinase inhibition decreases proinflammatory cytokines in human myeloid cells upon IL-1R stimulation. Altogether, our results expand the potential therapeutic use of salt-inducible kinase inhibitors in immune-mediated inflammatory diseases."

Journal • Biosimilar • Immunology