Merck KGaA

Technology for Serum and Glucocorticoid regulated kinase (SGK) inhibitors

Posted by Merck KGaAResponsive · Innovative Products and Technologies · Germany

Summary of the technology

Merck KGaA, Darmstadt, Germany, has developed and patented the results of its intense R&D activities for the identification of small organic molecules as SGK1 inhibitors. Based upon a rational screening cascade established, compounds have been identified and characterized with regard to their specific in vitro, cellular and in vivo activities. The package includes access to the IP, experimental results, and materials. Merck KGaA, Darmstadt, Germany, offers the unique chance to acquire this promising program.

Merck KGaA
Merck KGaA

Description of the technology

Serum and Glucocorticoid regulated kinases (SGK)

The serum and glucocorticoid-regulated kinases, isoforms 1, -2, and -3, belong to the group of so called AGC serine/threonine kinases. Isoform-1 (or SGK1) is a protein, which is expressed ubiquitously in eukaryotic cells. SGK1 activity is controlled on two levels: Its expression is under the control of cellular stress, e.g. cell shrinkage, and hormones, e.g. gluco- and mineralocorticoids. On the level of its enzymatic activity, SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase (PI3K) and 3- phosphoinositide dependent kinase-1 (PDK1).


Physiologic and pathophysiologic role of SGK1

SGK1 has been shown to be involved in the regulation of numerous ion channels (ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GlutR1, GlutR6), carriers (NHE3, GLUT1, SGLT1, EAAT1-5, Na+/K+-ATPase), enzymes (GSK3, NEDD4.2, phospho-mannose mutase-2) and transcription factors (FKHRL1, ß-catenin, NFB) (1). SGK1 contributes to renal Na+ absorption and K+
elimination, intestinal/renal glucose uptake (via regulation of SGLT1), tissue fibrosis, as well as mast cell activation and dendritic cell dampening (2)

Fig.1: Pathophysiological states with SGK1 dysregulation

SGK1 KO mice are resistant to insulin-dependent, salt sensitive increase in blood pressure (BP), mineralocorticoid stimulation of salt appetite, steroid induced tissue fibrosis, allergen induced anaphylactic/allergic shock, and LMCV induced hepatitis and cirrhosis.

In humans, a specific SGK1 gene polymorphism is present in about 5 % of the general population presumably causing increased SGK1 activity. SGK1 gene polymorphism carriers exhibit hypertension (linked with hyperinsulinemia), increased BMI and shortened QTinterval (3).

Fig.2: SGK1 is regulated both at the transcriptional as well as the post-translational level

SGK1 inhibition interferes with activated, not basal activity of its targets

Therapeutic use of SGK inhibitors

The inhibition of SGK1 by compounds according to inventions as described below (s. “Intellectual Property Status”) is a relevant therapy concept for treating illnesses and diseases such as diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiac circulatory diseases, kidney diseases, in general for all types of fibroses, inflammatory processes, tumors and tumor illnesses as well as viral diseases.
SGK1 has overlapping substrate specificity with Akt (or PKB), another AGC kinase with numerous targets related to cell survival, proliferation, translation and metabolism and motility (Biochem J 2013;452:499-508). Akt is believed to mediate many if not all of the PI3K/PDK1 mediated effects, both in normal development as well as in cancer. It has been shown that many breast cancer cell lines, which exhibit resistance to Akt-inhibition, express high levels of SGK1 and are sensitive to SGK1-knock-out or inhibition (Biochem J 2013;452:499-508). In the mouse model of insulin-dependent, salt sensitive increase in BP, the SGK1 inhibitor MSC2020151A (=EMD638683) exhibited pronounced anti-hypertensive effects (Cell Physiol Biochem 2011;28:137-146). In addition, the SGK-inhibitor EMD638683 has been shown to be effective in various cellular as well as in vivo models of cardiac hypertrophy (Cell Physiol Biochem. 2013;32:25-38), colon cancer (Cell Physiol Biochem. 2013;32:838-48), prostate cancer (FEBS Lett. 2014 May 2;588:1571-9) and pulmonary arterial hypertension (Cardiovasc Toxicol. 2014 epub May 14).

Description of the technology

Merck KGaA, Darmstadt, Germany, has developed and patented the results of its intense R&D activities for the identification of small organic molecules as SGK1 inhibitors. Based upon a rational screening cascade established, compounds have been identified and characterized with regard to their specific in vitro, cellular and in vivo activities. The package includes access to the IP, experimental results, and materials. Merck KGaA, Darmstadt, Germany, offers the unique chance to acquire this promising program.

Specifications

Specific SGK inhibitors have been developed, which inhibit the SGK enzyme isoforms in the nanomolare range. SGK1 has been shown to be involved in the regulation of numerous ion channels, carriers, enzymes and transcription factors (FASEB J. 2013;1:3-12). SGK1 contributes to renal Na+ absorption and K+ elimination, intestinal/renal glucose uptake, tissue fibrosis, as well as mast cell activation and dendritic cell dampening (FASEB J. 2013;1:3-12). SGK1 KO mice are resistant to insulin-dependent, salt sensitive increase in blood pressure (BP), mineralocorticoid stimulation of salt appetite, steroid induced tissue fibrosis, allergen induced anaphylactic/allergic shock, and LMCV induced hepatitis and cirrhosis. In humans, a specific SGK1 gene polymorphism is present in about 5 % of the general population presumably causing increased SGK1 activity. SGK1 gene polymorphism carriers exhibit hypertension (linked with hyperinsulinemia), increased BMI and shortened QT-interval (Curr Opin Nephrol Hypertens. 2009;18:439-48).

Main advantages of its use

  • Possibility to develop a novel rational treatment regime for hypertensive, diabetic patients with a polymorphism in the SGK1 gene (about 5 % of general population). Possibility to develop a novel treatment for breast cancer which exhibit an Akt/PKB resistance. Possibility to develop a novel treatment for pulmonary arterial hypertension.

Applications

  • SGK inhibitors are identified and developed for the use as therapeutics (both with regard to treatment of diseased humans as well sick animals). The SGK inhibitors are small organic molecules to be used as medications in all standard applications forms and formulations.

Patents


Merck has filed international patent applications in the field of SGK inhibitors.
The present innovations relate to compounds as described below, said derivates being kinase inhibitors with a high selectivity for SGKs.
Granted patents covering the 2 enantiomers of the most advanced compound MSC2020151A (= EMD638683) and additional structural derivates are still being maintained (WO2009/103484; WO2010/060522).


Fig. 3 MSC2020151A (=EMD638683)

WO2009/103484 (A1): SGK1 INHIBITORS FOR THE PROPHYLAXIS AND/OR THERAPY OF VIRAL DISEASES AND/OR CARCINOMAS

Fig. 4

WO2010/060522 (A1) DIFLUORPHENYL DIACYLHYDRAZIDE DERIVATES

The invention relates to novel difluorphenyl diacylhydrazide derivates of formula I, where R1, R2, R3, R4, R5, R6, and R7 have the meaning indicated in Claim 1, said derivates being kinase inhibitors and useable for treating illnesses and diseases such as diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonary hypertension, cardiac circulatory diseases, and kidney diseases, in general for all types of fibroses, inflammatory processes, tumors, and tumor illnesses.

Literature


(1) FASEB J. 2013;1:3-12
(2) Clin Exp Nephrol 2012;16:73–80
(3) Curr Opin Nephrol Hypertens. 2009;18:439-48
(4) Biochem J 2013;452:e11-e13
(5) Biochem J 2013;452:499-508
(6) Cell Physiol Biochem 2011;28:137-146
(7) Cell Physiol Biochem. 2013;32:25-38
(8) Cell Physiol Biochem. 2013;32:838-48
(9) FEBS Lett. 2014 May 2;588:1571-9
(10) Cardiovasc Toxicol. 2014 epub May 14

Terms

Merck is seeking partners, who are interested in acquiring this technology. The Terms concerning the transfer of technology and rights to the IPm and further joint development (if desired) are to be negotiated.

Technology Owner

Merck KGaA

Large Enterprise

Related keywords

  • Cytology, Cancerology, Oncology
  • Biology / Biotechnology
  • Biochemistry / Biophysics Technology
  • Cellular and Molecular Biology Technology
  • In vitro Testing, Trials Technology
  • Information and media, society
  • Biochemistry / Biophysics Market
  • Therapeutic
  • Pharmaceuticals/fine chemicals
  • Oncology
  • Endocrinology
  • Internal medicine
  • Cardiology
  • Pulmonary medicine
  • inflammation
  • metabolic syndrom
  • hypertension
  • viral deseases

About Merck KGaA

Large Enterprise from Germany

Merck KGaA, Darmstadt, Germany is a leading company for innovative and top-quality high-tech products in healthcare, life science and performance materials. Around 39,000 employees work in 65 countries to improve the quality of life for patients, to further the success of our customers and to help meet global challenges.

Legal Disclamer

There are two different, unaffiliated companies that use the name MERCK. Merck KGaA, Darmstadt, Germany, which operates this website, uses the firm name “Merck KGaA, Darmstadt, Germany,” in the United States and Canada, and also uses “EMD Serono” in biopharma, “MilliporeSigma” in life science and “EMD Performance Materials” in materials business. The other company, Merck & Co., Inc. holds the rights in the trademark MERCK in the United States and Canada. Merck & Co. is not affiliated with or related to Merck KGaA, Darmstadt, Germany, which owns the MERCK trademark in all other countries of the world. To reflect such fact and to avoid any confusion, certain logos, terms and business descriptions of the publications on this website have been substituted or modified, such as by referring to “Merck KGaA, Darmstadt, Germany” instead of “Merck” standing alone. Publications on this webpage, therefore, slightly deviate from the otherwise identical versions accessible outside the United States and Canada.

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