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Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

A heteroatom and hydrocarbon-based technology, applied in the field of small molecule inhibitors of lactate dehydrogenase and its application, can solve the problems of poor bioavailability of inhibitors

Active Publication Date: 2018-01-23
US DEPT OF HEALTH & HUMAN SERVICES +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the in vivo bioavailability of the inhibitor was found to be poor

Method used

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  • Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
  • Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
  • Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0299] This example describes the human LDHA primary biochemical assay used to characterize compounds of formula (I) in an embodiment of the invention.

[0300] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. 200 millimolar (mM) Tris HCl, pH 7.4, 100 micromolar (μM) EDTA and 0.01% TWEEN-20 TM , final concentration, used as assay buffer. LDHA reagent was 2 nanomolar (nM) human LDHA (Meridian Life Science, Inc., Memphis, TN), final concentration, in assay buffer. Substrate reagents were 0.06 mM NADH and 0.2 mM sodium pyruvate, final concentrations, in assay buffer. The resazurin / diaphorase coupling reagent was 0.037 mM resazurin and 0.133 milligrams per milliliter (mg / mL) diaphorase in assay buffer, final concentration. The sequence of steps, the amount and type of reagents required for each step and the timing are listed in Table 1. Inhibition of LDHA activity was measured by fluorescence emission.

[0301] Table 1

[...

Embodiment 2

[0304] This example describes the human LDHB enumeration screening biochemical assay used to characterize compounds of formula (I) in an embodiment of the invention.

[0305] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. 200 mM Tris HCl, pH 7.4, 100 μM EDTA and 0.01% TWEEN-20 TM , final concentration, used as assay buffer. LDHB reagent was 2 nM human LDHB (Meridian Life Science, Inc., Memphis, Tenn.), final concentration, in assay buffer. Substrate reagents were 0.13 mM NADH and 0.16 mM sodium pyruvate, final concentrations, in assay buffer. The resazurin / diaphorase coupling reagent is 0.037 mM resazurin and 0.133 mg / mL diaphorase, final concentration, in assay buffer. The sequence of steps, the amount and type of reagents required for each step and the timing are listed in Table 2. Inhibition of LDHB activity was measured by fluorescence emission.

[0306] Table 2

[0307]

Embodiment 3

[0309] This example describes the human PHGDH enumeration screening biochemical assay used to characterize compounds of formula (I) in an embodiment of the invention.

[0310] Test compounds were placed in Greiner Bio-One (Monroe, NC) 1536-well black solid bottom assay plates. 50mM TEA, pH 8.0, 10mM MgCl 2 , 0.05% BSA and 0.01% TWEEN-20 TM , the final concentration was used as the assay buffer. Substrate reagents were 10 μM EDTA, 0.625 mM glutamate, 500 nM human PSAT1, 500 nM human PSPH, 0.05 mM 3-phosphoglycerate kinase, 0.1 mM resazurin, and 0.1 mg / mL diaphorase, final concentrations, in assay buffer. PHGDH reagent is 0.15mM NAD + and 10 nM human PHGDH, final concentration, in assay buffer. The sequence of steps, the amount and type of reagents required for each step and the timing are listed in Table 3. Inhibition of PHGDH activity was measured by fluorescence emission.

[0311] table 3

[0312]

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Abstract

Provided is a compound of formula (I) [Formula (I) should be inserted here], in which Ar1, R1, U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I),including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and / or lactate dehydrogenase B (LDHB) activity in a cell.

Description

[0001] Citations to related applications [0002] This application claims priority to and benefit of US Provisional Application No. 62 / 097,226, filed December 29, 2014, which is hereby incorporated by reference in its entirety. Background technique [0003] Given the potential to preferentially target cancerous tissue over normal tissue, agents targeting enzymes involved in cancer cell metabolism present an attractive therapeutic avenue. While normal tissues typically use glycolysis only when oxygen availability is low, cancerous tissues rely heavily on aerobic glycolysis regardless of oxygen supply levels. This property is known as the Warburg effect (VanderHeiden et al., Science, 2009, 324(5930): 1029-1033). Lactate dehydrogenase (LDH) is involved in the final step of glycolysis, in which pyruvate is converted to lactate. A decreased rate of pyruvate entry into the TCA (tricarboxylic acid) cycle and a concomitant increase in lactate production are critical for tumor growth...

Claims

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Application Information

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IPC IPC(8): C07D417/04C07D417/14C07D403/04A61K31/427A61P35/00
CPCC07D403/04C07D417/04C07D417/14A61K31/415A61K31/4155A61K31/4178A61K31/422A61K31/427A61K31/437A61K31/4439A61K31/454A61K31/496A61K31/501A61K31/506A61K31/519A61K31/5355C07D231/20C07D231/38C07D401/04C07D403/06C07D409/04C07D413/04C07D471/04C07D495/04C07D495/14A61P35/00A61P43/00A61K45/06
Inventor 戴维·J·马洛尼阿吉特·贾达夫甘尼沙·雷·班图卡卢凯勒·瑞安·布里马科姆布赖恩·T·莫特杨世明丹尼尔·詹森·厄本胡新安顿·西梅奥诺夫珍妮弗·L·库茨内特索瓦亚历克斯·格雷戈里·沃特森加里·艾伦·苏利科夫斯基金光镐普拉门·克里斯托夫索姆纳特·贾纳维克托·M·达利-乌斯马尔威廉·J·穆尔伦纳德·M·内克斯希·V·丹格
Owner US DEPT OF HEALTH & HUMAN SERVICES
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