IC50: LYPLA1 (17 nM) and the related LYPLA2 (30 nM)
ML-211 is a dual inhibitor of LYPLA1 and the related LYPLA2.
Lysophospholipase 1 (LYPLA1), a protein palmitoyl thioesterase, is responsible for depalmitoylation of the oncogene HRas. Palmitoylation of such oncogenes is considered to be required for trafficking and malignant transformation, making LYPLA1 a promising target for downregulating oncogenic signaling.
In vitro: ML-211 was identified as a carbamate-based dual inhibitor of LYPLA1 and the related LYPLA2. ML-211 could inhibit the serine hydrolase ABHD11 with an IC50 value of 10 nM but was over 50-fold selective for LYPLA in a panel of 20 additional serine hydrolases. Given the high structural homology between LYPLA1 and LYPLA2, it was anticipated that ML211 modified LYPLA2 in an analogous manner. In additioin, out of more than 20 serine hydrolases (SHs), ML211 was observed to have one anti-target, alpha/beta hydrolase domain-containing protein 11 (ABHD11). ML211 and the anti-probe ML226 were evaluated for cell toxicity using both serum-free and serum-supplemented media, and the results showed that both compounds had a CC50 greater than 6 μM, which was 200-fold greater than the concentration necessary for complete inhibition of their respective target enzyme(s) [1].
In situ: It was found that both ML211 and ML226 were shown to be highly active in situ against their targets, completely inhibiting their target enzymes in serum-containing media after two hours at 30 nM concentration [1].
Clinical trial: So far, no clinical study has been conducted.
Reference:
[1] Adibekian, A. ,Martin, B.R.,Speers, A.E., et al. Optimization and characterization of a triazole urea dual inhibitor for lysophospholipase 1 (LYPLA1) and lysophospholipase 2 (LYPLA2). 1 R01 CA132630, 1-42 (2013).