Thiazole Derivatives as Inhibitors for the Treatment of Cancer Cells Resistant

Important Compound Classes

Title

1-H-Pyrazol-1-yl-thiazoles as Inhibitors of Lactate Dehydrogenase and Methods of Use Thereof

Patent Application Number

WO 2018/005807 A1

Publication Date

January 04, 2018

Priority Application

US 62/356,065

Priority Date

June 29, 2016

Inventors

Maloney, D. J.; Waterson, A. G.; Bantukallu, G. R.; Brimacombe, K. R.; Christov, P.; Dang, C. V.; Darley-Usmar, V. M.; Hall, M.; Hu, X.; Jadhav, A.; Jana, S.; Kim, K.; Moore, W. J.; Mott, B. T.; Neckers, L. M.; Simeonov, A.; Sulikowski, G. A.; Urban, D. J.; Yang, S. M.

Assignee Company

The United States of America, as represented by the Secretary, Department of Health and Human Services; Vanderbilt University; The UAB Research Foundation; and The Trustees of the University of Pennsylvania.

Disease Area

Cancer and fibrosis diseases

Biological Target

Lactate dehydrogenase

Summary

Lactate dehydrogenase (LDH) therapeutics represents an innovative approach to treat cancer because the peculiar glycolytic metabolism comprises the most invasive tumor cells. The transfer of hydride from one molecule to another in living cells is carried out by the enzyme dehydrogenase. The final step in the metabolic glycolysis pathway involves LDH in which pyruvate is converted to lactate. In normal tissues, glycolysis occurs when the oxygen supply is low, whereas in cancer tissue, aerobic glycolysis takes place regardless of the oxygen level. Consequently, the regulation of lactate production plays a crucial role in the growth and survival of tumors. The two subunits of LDH, LDHA and LDHB, have identical active sites. In cancerous patients, there is increased levels of the total serum LDH5, a tetramer of LHDA subunits. This upregulation allows cancer cells to metabolize lactate as an energy source. Therefore, inhibition of LDH reduces the ability of cancer cells to effectively metabolize lactate, thereby reducing proliferation and tumor growth. In this invention, compounds reported are potent inhibitors of LDH and provide methods for treating patients with cancer cells that are resistant to an anticancer agent.

Definitions

X is hydrogen or a halogen.

Y is hydrogen or C₁–C₂alkyl.

Z is −CO₂H, −CONH₂, −COCF₃, CH₂OH, or −B(OH)₂.

R₃ is a −C(O)CH₃, substituted or substituted phenyl, indanyl, tetrahydronaphthyl, cyclohexenyl, indenyl, imidazolyl, dihydrofuranyl, pyrrolidinyl, pyrimidinyl, thiazolyl, and so forth.

R₁₀ is substituted (cyclopropyl)C₀–C₄alkyl.

R is hydrogen, hydroxyl, C₁–C₄alkyl, or C₁–C₄alkoxy.

Key Structures

Biological Assay

The following assays were used to identify compounds of interest:

Human LDHA/LDHB/PHGDH/GAPDH primary biochemical assay was used to measure inhibition of LDHA/LDHB/PHGDH/GAPDH activity.

Cell-based HT lactate assay was employed in the colorimetric/fluorometric detection and characterization of the compounds shown in the invention.

Biological Data

The Table below, cellular inhibition of lactate production was given the following IC₅₀; +++ indicates <1 μM; ++ indicates 1–10 μM; + indicates 10–57 μM.

Recent Review Articles

• 1.El-Sisi A. E.; Sokar S. S.; Abu-Risha S. E.; El-Mahrouk S. R.. Biomed. Pharmacother. 2017, 95, 1565.
• 2.Rani R.; Kumar V.. Future Med. Chem. 2017, 9, 1113.
• 3.Manerba M.; Di Ianni L.; Govoni M.; Roberti M.; Recanatini M.; Di Stefano G.. Eur. J. Pharm. Sci. 2017, 96, 37.
• 4.Maftouh M.; Avan A.; Sciarrillo R.; Granchi C.; Leon L. G.; Rani R.; Funel N.; Smid K.; Honeywell R.; Boggi U.; Minutolo F.; Peters G. J.; Giovannetti E.. Br. J. Cancer. 2014, 110, 172.

The author declares no competing financial interest.