Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Kinase Inhibitors for Treatment of Cancer and Inflammation Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States to IKKα and IKKβ are the IKKε and TBK1 (TANK-binding kinase), they activate the critical interferon response factor 3 (IRF3) and IRF7. Large amount of data has shown the importance of these kinases in various physiological and pathophysiological functions such as inflammation, cell survival, cancer, metabolic regulation, neuroadaptation, and defense response. Consequently, inhibition of IKKε and/or TBK1 may show efficacy in the treatment of various diseases such as breast cancer, ovarian cancer, obesity, asthma, psoriasis, Crohn’s disease, and septic shock. Another key role that IKKε and TBK1 play involves the production of type 1 interferons and the stimulation of interferon Signature Genes (ISGs). The upregulation of type 1 interferon or ISG has been associated with disease processes such as interferonopathies or systemic lupus erythematosus, respectively. The salt-inducible kinases (SIK) constitute a serine/ threonine kinase subfamily that belongs to the AMP-activated protein kinase (AMPK) family, which constitute three members (SIK1, -2, and -3). Inhibitory phosphorylation of SIKs by protein kinase A (PKA) in response to elevated cAMP enables the CREB-regulated transcriptional coactivators (CRTCs) and HDACs to enter the nucleus in order to coordinate the regulation of gene expression. SIK2 play a role in the modulation of macrophage signaling pathways and function to restrict the formation of regulatory phenotypes by limiting production of anti-inflammatory cytokines such as IL-10, and consequently upregulate the production of inflammatory cytokines, including IL-12 and TNF-α. Therefore, inhibition of SIK2 is used in the treatment of inflammation disorders such as autoimmune diseases. There are multiple disease states that are mediated by IKKε, TBK1, and/or SIK2 mechanisms, including rheumatoid arthritis, inflammatory bowel disease, inflammatory and tissue repair disorders, lupus, acquired immune deficiency syndrome, obesity, diabetes, Alzheimer’s disease, stroke, and so forth. The compounds represented in this Patent Highlight may find utility in patient populations where aberrant IKKε, TBK1, and/or SIK2 activity leads to these disease processes.
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Important Compound Classes.
Title. 5-(Pyrimidin-4-yl)-2-(pyrrolidin-1-yl)nicotinonitrile Compounds as IKKε, TBK1 and/or SIK2 Kinases Inhibitors Patent Application Number. WO 2018/154315 A1 Publication Date. August 30, 2018 Priority Application. 1702947.1 GB Priority Date. February 23, 2017 Inventors. Newton, G. K.; Stewart, M. R. Assignee Company. Domainex Limited. Disease Area. Cancer Biological Target. IKKε, TBK1, and/or SIK2 kinases Summary. There are large number of genes involved in immune responses, cell survival, inflammation, and cancer, which are regulated by members of the nuclear factor kappa B (NF-κB), a family of dimeric transcription factors (TFs). In response to various stimuli such as cytokines, infectious agents, and DNA double-strand damage, NF-κB TFs are rapidly activated and phosphorylate the inhibitory IκB proteins. The IκB bound NF-κB TFs drive expression of target genes in the nucleus. Two protein kinases with a high degree of sequence similarity but nonoverlapping functions, IκB kinases (IKKα and IKKβ) mediate the phosphorylation of IκB proteins. In addition, two protein kinases that exhibit structural similarity
Received: October 13, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acsmedchemlett.8b00481 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Notes
Key Structures.
The author declares no competing financial interest.
Biological Assay. The IKKε and TBK1 enzyme potency for compounds in this Patent Highlight were tested using a time-resolved fluorescence-based Lanthascreen assay. The SIK2 enzyme potency was measured using radiolabeled 33P-ATP by means of the Kinase HotSpot technology. Biological Data. The Table below shows observed enzyme potency for IKKε, TBK1, and SIK2 IC50 values for the compounds of this Patent Highlight. The pharmacokinetic evaluation was performed using female Balb-C mice. Recent Review Articles. 1. Yu, H.; Cleveland, D. W. Trends Pharmacol. Sci. 2018, 174, 1339. 2. Yu, H.; Cleveland, D. W. Cell 2018, 174, 1339. 3. Klaeger, S.; Heinzlmeir, S.; Wilhelm, M.; et al. Science 2017, 358, 1148. 4. Nandipati, K. C.; Subramanian, S.; Agrawal, D. K. Mol. Cell. Biochem. 2017, 426, 27.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 B
DOI: 10.1021/acsmedchemlett.8b00481 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
