KEA1-97 targets lysine 72 of thioredoxin. It disrupts the interaction ofthioredoxin withcaspase 3, activates caspases, and induces apoptosis without affectingthioredoxin activity.
Thioredoxin is an endogenous protein with antioxidant and antiapoptotic activity in a variety of tissues Zhuming Yin,et al. Thioredoxin Protects Skin Flaps from Ischemia-Reperfusion Injury: A Novel Prognostic and Therapeutic Target.. Caspase-3 (Casp-3) is an enzyme that efficiently induces apoptosis, a form of programmed cell death[1]. The EC(50) for caspase-3 activation by reduced thioredoxin-1 was 2.5 mM, by reduced glutathione 1.0 mM and by dithiothreitol 3.5 mM. A catalytic site redox-inactive mutant thioredoxin-1 was almost as active as thioredoxin-1 in activating caspase-3. Caspase activation was shown to correlate with the number of reduced cysteine residues in the thioredoxins. Reduced insulin and serum albumin were as effective on a molar basis as thioredoxin-1 in activating caspase-3[2]. Compared with the model group, the mRNA expression of caspase-3 and the protein levels of caspase-3 and cleaved-caspase-3 were notably elevated in the Weimaining group. After in vivo bioluminescent imaging, the total photon number of the Weimaining group was found to be lower than that of the LWMH group on day 14 after administration. Additionally, the AI and expression levels of caspase-3 mRNA, caspase-3, and cleaved-caspase-3 protein of the WMN group were higher than those of the LWMH group. Kea1-97 is a selective disruptor of interaction between thioredoxin and caspase-3 (IC50 = 10 μM)[3]. KEA1-97 disrupts the interaction of thioredoxin with caspase 3, activates caspases, and induces apoptosis without affecting thioredoxin activity. Moreover, KEA1-97 impairs in vivo breast tumor xenograft growth. KEA1-97 impairs 231MFP TNBC survival and proliferation without significantly affecting nontransformed MCF10A cell viability and that KEA1–97daily treatment at 5 mg/kg ip is well-tolerated in mice[4].
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