Project: Optimization of inhibitors of the glycolytic enzyme Lactate Dehydrogenase A for the treatment of cancer
Background_x000D__x000D_Unlike normal cells, cancer cells have an unusual metabolic profile, exhibiting an addiction to glucose and a high rate of aerobic glycolysis to supply them with sufficient energy to meet their needs for rapid growth.This phenomenon, known as the 'Warburg Effect' is independent of the availability of oxygen and results in increased levels of lactate and low ATP production. This metabolic trait confers advantages to cancer cells by establishing a means of providing building blocks to support biomass synthesis for growth and proliferation whilst still supplying the cells with sufficient energy production even in the hypoxic environments often encountered in tumor tissue. The enhanced glucose uptake that accompanies the elevated rate of glycolysis in cancer cells is utilized to image cancers in the clinic using the glucose analog 2-(18F)-fluoro-2-deoxy-D-glucose (FDG) by positron emission tomography (PET) and is the most commonly used tumor diagnostic tool. However, this altered metabolism makes cancer cells more dependent on their primary energy source, glucose, than normal cells. Indeed, cancer cells are highly susceptible to glucose withdrawal and this phenomenon of ‘glucose addiction’ is considered to be an Achilles’ Heel of cancer._x000D_ _x000D_The identification of molecules that can modulate the activity of key enzymes involved in the altered metabolic state exhibited by many tumor types has received much attention from the pharmaceutical industry in recent times. The enzyme lactate dehydrogenase A (LDHA) catalyses the conversion of the end product of glycolysis, pyruvate to lactate with the recycling of NADH back to NAD+. LDHA is now considered a key protein involved in the ability of cancer cells to fuel themselves and sustain their exaggerated growth. LDHA has been identified as a key target in cancer metabolism as it is frequently up-regulated in clinical tumors, used as a biomarker for tumour progression, and its inhibition in cancer cells by siRNA or small molecule tool compounds has been reported to induce oxidative stress and cell death. LDHA also makes a vital contribution to COtaining the redox potential of cancer cells by consuming NADH and regenerating NAD+. LDHB is closely related to LDHA and primarily expressed in the heart, suggesting LDHA-selective compounds would be desirable. As such, an LDHA inhibitor would potentially have therapeutic benefit in a number of different cancer indications, including lung cancer (NSCLC), breast cancer, renal cell carcinoma, pancreatic cancer, ovarian, glioma and human lymphoma. _x000D__x000D_Goals_x000D__x000D_A successful outcome to the project would generate at least one novel small molecule pre-clinical candidate inhibitor of LDHA as a potential new treatment for cancer. The molecule would have the necessary drug-like qualities such that a licensing deal with a large pharmaceutical company could be carried out at this stage and clinical trials could be initiated within 2 years of project completion. We are looking to preferably deliver an orally available molecule. To achieve this goal, 5 pre-existing novel chemical series of LDHA inhibitors will be taken into an optimization program. The project will initially optimize the in vitro potency of the template compounds by investigating the structure activity relationships across custom designed and synthesized analogues using in vitro techniques. The techniques used will be an enzymatic assay of LDH inhibition , cell-based assay of inhibition of lactate production (the product of LDH enzymatic activity) in cancer cells, and imaging of various parameters of cancer cell growth following compound treatment. The molecules will be engineered to possess drug-like qualities enabling the rapid initiation of a clinical development program following project completion. _x000D__x000D_Project Consortium_x000D__x000D_The program of work will encompass a 24 month joint discovery research project between UK-based TPP Global Development and its Dutch and UK Ps to utilise innovative structure-based drug design, medicinal chemistry and cancer cell imaging technology platforms to develop novel LDHA inhibitors. Each company offers proven and complimentary expertise to maximize the chances of success. TPP Global Development, as the lead P, brings a wealth of small molecule drug discovery and development knowledge to the project; Mercachem is a leading European medicinal chemistry organization with a proven track record of using innovative structure and computational drug design techniques to develop small molecule inhibitors from existing chemical scaffolds to clinical candidate selection. Essen Bioscience provides a state-of-the-art live cancer cell imaging technology which allows multiple parameters of cell health to be measured simultaneously. Such high-throughput real-time imaging technology provides an innovative tool to generate kinetic data and enable the rapid progression of molecules through pre-clinical drug discovery.
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Acronym
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LDHA Inhibitors
(Reference Number: 8171)
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Duration
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02/09/2013 - 28/08/2015
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Project Topic
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The project will be a two year drug discovery program to utilise innovative structure-based drug design, medicinal chemistry and cancer cell imaging technology platforms to develop and optimize first-in-class selective inhibitors at a key metabolic enzyme, LDHA, as novel oncology therapeutics.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
