1. CPI-613(Devimistat ) is an E1 pyruvate dehydrogenase (PDH) modulator that prevents cancer cells from metabolizing glucose for energy. CPI-613 has been granted orphan drug status by the US FDA for pancreatic cancer.
CPI-613(Devimistat ) is a first in class agent that targets mitochondrial metabolism through inhibition of pyruvate dehydrogenase and a-ketogluterate dehydrogenase.
2. CPI-613(Devimistat ) is a lipoate derivative synthesized to be catalytically inert but to potentially mimic lipoate catalytic intermediates. The drug is in phase II of clinical trials for the treatment of Myelodysplastic syndromes; Pancreatic cancer; Small cell lung cancer; Solid tumors; Bile duct cancer; Acute Myeloid leukemia. The mechanism of CPI-613(Devimistat ) action can be explained by (I) inhibition of tumor cell pyruvate dehydrogenase complex (PDC) through activation of pyruvate dehydrogenase kinases leading to inactivating phosphorylation of the E1alpha-subunit of PDC; and (II) inhibition of alpha-ketoglutarate dehydrogenase.
Patients with bile duct cancer receive CPI-613(Devimistat ) IV over 2 hours on days 1-5, 1 week prior to course. After that, they receive the drug IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses. Patients with pancreatic cancer, small cell lung cancer, AML, and Myelodysplastic Syndrome receive 3,000 mg/m2 CPI-613 infused IV over 2 hours on Days 1 and 4 of each of the 3 treatment weeks.
Route of Administration: Intravenous
In the ATP production assay, H460 cells were seeded at 10,000 cells per well in RPMI (11 mM glucose, 2 mM glutamine) medium and grown overnight. The medium was then changed to RPMI without glucose and containing 10 mM pyruvate and 2 mM glutamine alone or together with 0.1 mM water soluble oleic acid. After 24 hours, the medium was replaced with fresh RPMI without glucose and containing either 10 mM pyruvate and 2 mM glutamine or 0.1 mM oleic acid and 0.5 mM aspartate (matched to overnight adaptation) and containing CPI-613(Devimistat ) (240 uM) in the treated samples for 2 hours before ATP level measurements.