KSC-34
目录号 : GC61579KSC-34是蛋白质二硫键异构酶A1(PDIA1)的共价修饰剂,是一种有效的PDIA1a位点选择性抑制剂,IC50为3.5μM。KSC-34对a′结构域的选择性为30倍。KSC-34在复杂蛋白质组中对PDIA表现出选择性。
Cas No.:2226201-97-2
Sample solution is provided at 25 µL, 10mM.
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KSC-34, a covalent modifier of protein disulfide isomerase A1 (PDIA1), is also a selective and potent a-site inhibitor of PDIA1 with an IC50 of 3.5 μM. KSC-34 displays a 30-fold selectivity for a domain over a′ domain and displays high selectivity for PDIA1 in complex proteomes with minimal engagement of other members of the PDI family[1].
KSC-34 is selective for PDIA1 over other members of the PDI family, and other cellular cysteine-containing proteins. KSC-34 contains a (4-phenylbutyl)methylamine diversity element for optimized binding to the active site of the a domain of PDIA1 with a chloroacetamide electrophile for covalent modification of C53 on PDIA1[1].
[1]. Cole KS, et al. Characterization of an A-Site Selective Protein Disulfide Isomerase A1 Inhibitor. Biochemistry. 2018;57(13):2035-2043.
Cas No. | 2226201-97-2 | SDF | |
Canonical SMILES | O=C(NCCNC1=NC(N(C)CCCCC2=CC=CC=C2)=NC(NCC#C)=N1)CCl | ||
分子式 | C21H28ClN7O | 分子量 | 429.95 |
溶解度 | DMSO: 100 mg/mL (232.59 mM) | 储存条件 | 4°C, stored under nitrogen |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.3259 mL | 11.6293 mL | 23.2585 mL |
5 mM | 0.4652 mL | 2.3259 mL | 4.6517 mL |
10 mM | 0.2326 mL | 1.1629 mL | 2.3259 mL |
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Characterization of an A-Site Selective Protein Disulfide Isomerase A1 Inhibitor
Biochemistry 2018 Apr 3;57(13):2035-2043.PMID:29521097DOI:PMC5884060
Protein disulfide isomerase A1 (PDIA1) is an endoplasmic reticulum (ER)-localized thiol-disulfide oxidoreductase that is an important folding catalyst for secretory pathway proteins. PDIA1 contains two active-site domains (a and a'), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. The two active-site domains share 37% sequence identity and function independently to perform disulfide-bond reduction, oxidation, and isomerization. Numerous inhibitors for PDIA1 have been reported, yet the selectivity of these inhibitors toward the a and a' sites is poorly characterized. Here, we identify a potent and selective PDIA1 inhibitor, KSC-34, with 30-fold selectivity for the a site over the a' site. KSC-34 displays time-dependent inhibition of PDIA1 reductase activity in vitro with a kinact/ KI of 9.66 × 103 M-1 s-1 and is selective for PDIA1 over other members of the PDI family, and other cellular cysteine-containing proteins. We provide the first cellular characterization of an a-site selective PDIA1 inhibitor and demonstrate that KSC-34 has minimal sustained effects on the cellular unfolded protein response, indicating that a-site inhibition does not induce global protein folding-associated ER stress. KSC-34 treatment significantly decreases the rate of secretion of a destabilized, amyloidogenic antibody light chain, thereby minimizing pathogenic amyloidogenic extracellular proteins that rely on high PDIA1 activity for proper folding and secretion. Given the poor understanding of the contribution of each PDIA1 active site to the (patho)physiological functions of PDIA1, site selective inhibitors like KSC-34 provide useful tools for delineating the pathological role and therapeutic potential of PDIA1.