malonyl-coenzyme-a and Neoplasms

The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.

Topics: Administration, Oral; Animals; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Fatty Acid Synthases; Half-Life; Humans; Malonyl Coenzyme A; Mice; Mice, Nude; Molecular Docking Simulation; Neoplasms; Piperazines; Protein Structure, Tertiary; Rats; Structure-Activity Relationship

We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues. Accordingly, this led us to discover a novel 1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1k as a promising ACC1 inhibitor, which showed potent ACC1 inhibition as well as sufficient cellular potency. Since compound 1k displayed favorable bioavailability in mouse cassette dosing PK study, we conducted in vivo Pharmacodynamics (PD) studies of this compound. Oral administration of 1k significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at a dose of 100 mg/kg. Accordingly, our novel series of potent ACC1 inhibitors represent useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.

Topics: Acetyl-CoA Carboxylase; Administration, Oral; Amides; Animals; Drug Design; Enzyme Inhibitors; HCT116 Cells; Humans; Male; Malonyl Coenzyme A; Mice; Mice, Inbred ICR; Neoplasms; Pyridines; Structure-Activity Relationship; Transplantation, Heterologous

The alterations of enzymatic activities involved in lipid degradation in cancer cachexia have not been fully elucidated. One of the two subclones of colon 26 adenocarcinoma, clone 20, with a potent ability to induce cachexia, or clone 5, without such an activity, was transplanted in to CDF-1 male mice. Murine livers were extirpated for analyses on the 14th day after tumor inoculation. The body weights and food intake of mice bearing clone 20 were all significantly lower than those of non-tumor bearing mice and mice bearing the clone 5 tumor. The decline of body weight was accompanied by a shrinkage of epididymal fat pads. Expression of spermidine/spermine N-1 acetyl transferase (SSAT) assessed by real-time PCR was significantly increased in cachectic mice. Conversely, acetyl-CoA carboxylase (ACC) measured by Western blotting and malonyl-CoA levels determined by malonyl-CoA:acetyl-CoA cycling procedures were decreased in cachectic mice. Indomethacin in drinking water reversed the clone 20 induced decrease in body and fat weight and food intake, and simultaneously negated the clone 20 induced increase of SSAT expressions and decrease of ACC and malonyl-CoA amounts. Because malonyl-CoA inhibits the rate-limiting step in the beta-oxidation of fatty acids, the decreased malonyl-CoA and the background metabolic alterations may contribute to the accelerated lipolysis of cancer cachexia.

Topics: Acetyl-CoA Carboxylase; Acetyltransferases; Animals; Body Weight; Cachexia; Disease Models, Animal; Eating; Liver; Male; Malonyl Coenzyme A; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasms; Polymerase Chain Reaction

Topics: Adenylate Kinase; Animals; Central Nervous System; Eating; Energy Metabolism; Heart; Humans; Malonyl Coenzyme A; Mice; Neoplasms