Takeshi Sagara

Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.

Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G2 checkpoint signaling. Because p53 is a key regulator in the G1 checkpoint, p53-deficient tumors rely only on the G2 checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies. [Mol Cancer Ther 2009;8(11):2992–3000]

Design and synthesis of 10-oxo derivative of N-cyclopropylmethyl (−)-6β-acetylthiodihydro-normorphine, a potentially κ-selective opioid receptor ligand

Abstract The design and synthesis of 10-oxo derivative of N -cyclopropylmethyl-(−)-6β-acetylthio dihydronormorphine ( 4 ) are described. The result of pharmacological assays indicate that compound 4 acts as a μ-opioid receptor antagonist and κ-opioid receptor agonist which is suggested to be more potent analgesic action than that of 1 and morphine through an activation of κ-opioid receptors.

A new class of type I protein geranylgeranyltransferase (GGTase I) inhibitor.

Replacement of the thiol groups in 1, a potent and highly selective Candida albicans GGTase I inhibitor discovered through screening, with an imidazole ring was achieved by using solid phase synthesis. A non-thiol compound, 7, was found as a representative of a new class of potent C. albicans GGTase I inhibitor with high selectivity against human GGTase I.

Specific affinity labeling of μ opioid receptors in rat brain by S-activated sulfhydryldihydromorphine analogs

Abstract S -Activated sulfhydryldihydromorphine analogs 1 and 2 were synthesized. In the rat brain receptor binding assays, both 1 and 2 exhibited considerably high affinities for μ opioid receptors (IC 50 ; 1 = 31.1 nM, 2 = 10.7 nM). However, when each analog was incubated with membranes for the purpose of getting disulfide bridgings, 1 ( EC 50 = 58 nM) was found to affinity-label the μ receptors about 30 times more effectively than 2 ( EC 50 = 1700 nM).