Novel Substituted Tetrazoles as ACSS2 Inhibitors for Treating Cancer

Important Compound Classes

Title

Tetrazole Derivatives

Patent Publication Number

WO 2021/185793 A1

Publication Date

September 23, 2021

Priority Application

EP 20164206.3

Priority Date

March 19, 2020

Inventors

Fuchss, T.; Koetzner, L.; Schindler, C.; Kuhn, D.

Assignee Company

Merck Patent GmbH, Germany and Ryvu Therapeutics S.A., Poland

Disease Area

Cancer

Biological Target

Acetyl-CoA synthetase 2 (ACSS2)

Summary

It is well-established that the rapid and uncontrolled growth of tumors and proliferation of cancer cells require increased energy (ATP) and biomass (lipid) production when compared to normal and healthy cells.

In the recent years, the role of acetate metabolism for cancer cell proliferation has become of growing interest in cancer research and development of cancer therapy. It has been shown that some tumors primarily utilize acetate for energy production, while others mainly use it for lipid (i.e., biomass) synthesis or regulation of histone acetylation and thus gene transcription. In all of these processes, acetate is converted into acetyl-CoA by means of acetyl-CoA synthetase (ACSS), either by the mitochondria-localized acetyl-CoA synthetase 1 (ACSS1) or nucleocytosol-localized acetyl-CoA synthetase 2 (ACSS2). Thus, acetyl-CoA is an important metabolite of cancer cells not only with regard to energy production in the mitochondrion but also with regard to lipid and fatty acid synthesis in the cytosol of cancer cells as well as the histone acetylation in the nucleus of the cell.

Studies have shown that ACSS2 is highly expressed in many cancer tissues. These findings and the fact that it is upregulated by hypoxia and low nutrient availability make ACSS2 an attractive target for cancer treatment.

The present application describes a series of tetrazoles as ACSS2 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = Ar_A or Hetar_A;

R₂ = Ar_B or Hetar_B;

R₃ = C_1–6-aliphatic or −O-C_1–6-aliphatic;

R₄ = H, D, C_1–6-aliphatic or −O-C_1–6-aliphatic; and

R₅ = H, D, C_1–6-aliphatic, −O-C_1–6-aliphatic or halogen.

Key Structures

Biological Assay

The biochemical activity ACSS2 assay, ACSS2 cellular lipid assay, and ACSS2 cellular histone assay were performed. The compounds described in this application were tested for their ability to inhibit ACSS2. The ACSS2 biochemical IC₅₀ (nM), ACSS2 cellular lipid IC₅₀ (nM), and ACSS2 cellular histone IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for ACSS2 inhibition. The biological data obtained from testing representative examples are listed in the following table.

For IC₅₀: “A” means 0.01 nM to <1 nM; “B” means 1 nM to <10 nM; “C” means 10 nM to <100 nM; “D” means 100 nM to <10000 nM.

Claims

Total claims: 16

Compound claims: 12

Pharmaceutical composition claims: 2

Method for manufacturing claims: 1

Kit claims: 1

Recent Review Articles

• 1.Bradshaw P. C.Antioxidants 2021, 10, 572.
• 2.Bacci M.; Lorito N.; Smiriglia A.; Morandi A.. Trends Cancer 2021, 7, 198.
• 3.Siklos M.; Kubicek S.. FEBS J. 2021, in press.
• 4.Pan C.; Li B.; Simon M. C.. Mol. Cell 2021, 81, 3760.
• 5.Nitsch S.; Shahidian L. Z.; Schneider R.. EMBO Rep. 2021, 22, e52774.
• 6.Trefely S.; Lovell C. D.; Snyder N. W.; Wellen K. E.. Mol. Metab. 2020, 38, 100941.

The author declares no competing financial interest.