Cellular Processes

We considered [6,6] heterocyclic ring systems as alternatives to the [6,5] ring systems present in compounds 1C2, expecting divergence of SAR and possibly favoring side chains and substituents that would positively alter the physical properties of the resulting MCT1 inhibitors

We considered [6,6] heterocyclic ring systems as alternatives to the [6,5] ring systems present in compounds 1C2, expecting divergence of SAR and possibly favoring side chains and substituents that would positively alter the physical properties of the resulting MCT1 inhibitors. A core structure of particular interest was the pteridine scaffold 5, a heterocyclic core that is present in many natural products26?29 and that has been widely used in drug discovery efforts.30?32 Accordingly, we targeted appropriately substituted pteridine trione/dione MK-5172 scaffolds MK-5172 6 and 7 (Physique ?(Figure2).2). phosphorylation to produce energy for maintenance of cellular functions.1,2 Indeed, malignancy cells have up to a 60-fold enhanced rate of glycolysis relative to normal cells, even with sufficient oxygen.1 This dependence upon glycolysis, and its effects, is termed the Warburg effect.2 Highly glycolytic cells produce excessive amounts of lactate, the end product of glycolysis, which is actively transported out of the cell to normalize intracellular pH levels. Lactate homeostasis is usually managed via a family of 12-membrane pass cell surface proteins coined monocarboxylate transporters (MCTs; also known as the SLC16a transporter family). Fourteen MCTs are known, but only MCT1, MCT2, MCT3, and MCT4 transport small monocarboxylates such as lactate, pyruvate, and ketone body (acetoacetate and -hydroxybutyrate) across plasma membranes in a proton-linked exchange.3 Expression profiling studies have established that most aggressive tumor types express markedly elevated levels of MCT1, MCT4, or both. Notably, the expression of MCT1 and MCT4 is usually regulated by two major oncogenic transcription factors, and hypoxia inducible factor-1 (HIF-1), respectively,4,5 that direct marked increases in the production of important proteins that support aerobic glycolysis, including amino acid transporters and enzymes involved in the catabolism of glutamine and glucose. 6 Malignancies having involvement and hypoxic tumors are generally resistant to current frontline therapies, with high rates of treatment failure, relapse, and high patient mortality.7,8 Importantly, inhibition of MCT1 or MCT4 can kill tumor cells ex vivo and provoke tumor regression in vivo,4,9 and their potency is augmented by agents such as metformin Rabbit Polyclonal to HEY2 that force a glycolytic phenotype upon the cancer cell.4 Many weak MCT1 inhibitors (i.e., those effective at high micromolar levels) have been explained, including -cyano-4-hydroxycinnamate,10,11 stilbene disulfonates,12 phloretin,13 and related flavonoids.14 Coumarin-derived covalent MCT inhibitors have also recently been disclosed.15,16 The most potent known MCT1 inhibitors are the pyrrolopyridazinones and the thienopyrimidine diones (e.g., compounds 1C2, Figure ?Physique11).17?22 Indeed, compound 2 has advanced into phase I clinical trials for treating some human malignancies.23,24 These compounds, and to our knowledge all MCT1 MK-5172 inhibitors yet explained, are dual MCT1/MCT2 inhibitors. MCT2 has very high sequence homology with MCT1, yet it likely has a smaller role than MCT1 and MCT4 for monocarboxylate transport in human cancers based upon expression studies. However, MCT2 inhibition may play a role in potential off-target effects of current brokers that could arise from blocking lactate transport in MK-5172 normal cells. Open in a separate window Physique 1 Potent MCT1 inhibitors. Improved MCT1 inhibitors could be accessed by performing additional structure activity relationship (SAR) studies around scaffold 1. Indeed, toward this goal we have made some refinements in Astra-Zenecas initial synthetic strategy for 1.25 However, a more desirable approach is to seek alternative scaffolds for MCT1 inhibition that are readily synthesized and that may form similar transporter contacts as do compounds 1C2. We considered [6,6] heterocyclic ring systems as alternatives to the [6,5] ring systems present in compounds 1C2, expecting divergence of SAR and possibly favoring side chains and substituents that would positively alter the physical properties of the producing MCT1 inhibitors. A core structure of particular interest was the pteridine scaffold 5, a heterocyclic core that is present in many natural products26?29 and that has been widely used in drug discovery efforts.30?32 Accordingly, we targeted appropriately substituted pteridine trione/dione scaffolds 6 and 7 (Determine ?(Figure2).2). Routes to 6,7-disubsituted pteridines have been reported,33?38 but to our knowledge the synthetic chemistry of substituted pteridinone scaffolds 6C7 has not been explored. Here we report the synthesis of these substituted pteridinone scaffolds and their activity as MCT1-specific lactate transport inhibitors that selectively block the growth of MCT1-expressing human lymphoma cells. Open in a separate window Physique 2 Possible MCT inhibitor scaffolds 6 and 7. Results From an efficiency standpoint, it.