KLH45

KLH45 is an inhibitor of the phospholipase DDHD domain containing 2 (DDHD2; IC₅₀ = 1.3 nM).¹ It is selective for DDHD2 over greater than 50 serine hydrolases, including DDHD1 and Sec23ip, but does inhibit α/β-hydrolase domain-containing protein 6 (ABHD6). It inhibits DDHD2 and ABHD6 in Neuro2A cells when used at a concentration of less than 10 nM and inhibits DDHD2 by greater than 95% at a concentration of 25 nM. KLH45 (2 µM) prevents increases in triacylglycerol (TAG) hydrolase activity in HEK293T cell lysates expressing recombinant DDHD2 and incubated with a radiolabeled TAG substrate. It decreases TAG levels in the CNS of mice when administered at a dose of 20 mg/kg twice per day for four days. KLH45 (2 µM) also reverses DDHD2-induced lipid droplet reduction in COS-7 cells expressing recombinant DDHD2 and loaded with oleic acid.²

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1. Inoles, J.M., Hsu, K.L., Dix, M.M., et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc. Natl. Acad. Sci. USA 111(41), 14924-14929 (2014).

2. Inloes, J.M., Kiosses, W.B., Wang, H., et al. Functional contribution of the spastic paraplegia-related triglyceride hydrolase DDHD2 to the formation and content of lipid droplets. Biochemistry 57(5), 827-838 (2018).