Ezatiostat hydrochloride (TER199; TLK199 hydrochloride) is a tripeptide analog of glutathione and is a selective and orally activeglutathione S-transferase P1-1 (GSTP1)inhibitor. Ezatiostat hydrochloride leads toJNKactivation by inhibitingGSTP1. Ezatiostat hydrochloride stimulates both lymphocyte production and bone marrow progenitor proliferation. Ezatiostat hydrochloride has the potential for myelodysplastic syndrome (MDS) treatment^[1][2].

Glutathione S-transferase P1-1 (GSTP1)^[1]

Ezatiostat causes dissociation of the enzyme from the jun-N-terminal kinase/c-Jun (JNK/JUN) complex, leading to JNK activation by phosphorylation. The therapeutic action of ezatiostat appears to include both proliferation of normal myeloid progenitors as well as apoptosis of the malignant clone^[1].
Selection of a resistant clone of an HL60 tumor cell line through chronic exposure to Ezatiostat (TLK199) results in cells with elevated activities of c-Jun NH2 terminal kinase (JNK1) and ERK1/ERK2, and allowes the cells to proliferate under stress conditions that induced high levels of apoptosis in the wild type cells^[2].

Administration of Ezatiostat (TLK199), stimulates both lymphocyte production and bone marrow progenitor (colony-forming unit-granulocyte macrophage) proliferation, but only in glutathione S-transferase P1-1 (GSTP1^+/+) and not in GSTP1^-/-animals^[2].

566.11

C₂₇H₃₆ClN₃O₆S

286942-97-0

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