Yuji Koriyama, Akihiro Hori, Hisanori Ito, Shuji Yonezawa, Yoshiyasu Baba, Norihiko Tanimoto, Tatsuhiko Ueno, Shiho Yamamoto, Takahiko Yamamoto, Naoya Asada, Kenji Morimoto, Shunsuke Einaru, Katsunori Sakai, Takushi Kanazu, Akihiro Matsuda, Yoshitaka Yamaguchi, Takuya Oguma, Maarten Timmers, Luc Tritsmans, Ken-Ichi Kusakabe, Akira Kato and Gaku Sakaguchi : Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial., Journal of Medicinal Chemistry, Vol.64, No.4, 1873-1888, 2021.
(要約)
demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.
Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.
Yoshiyasu Baba, Nozomu Hirukawa and Mikiko Sodeoka : Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin): implications for the binding mode., Bioorganic & Medicinal Chemistry, Vol.13, No.17, 5164-5170, 2005.
(要約)
Cantharidin is well known as a potent serine/threonine protein phosphatase 1 and 2A (PP1 and PP2A) inhibitor, with less potent inhibitory activity for PP2B, which regulates T-cell proliferation. We synthesized and evaluated four optically pure stereoisomers of 1-substituted norcantharidin analogues. The absolute stereochemistry of each stereoisomer was determined based on X-ray crystal structure analysis. Remarkably, optically active cantharidin analogues having (1S)-configuration showed selective inhibition of PP2B, without inhibiting PP1 or PP2A.
Yoshiyasu Baba, Yosuke Ogoshi, Go Hirai, Takeshi Yanagisawa, Kumiko Nagamatsu, Satoshi Mayumi, Yuichi Hashimoto and Mikiko Sodeoka : Design, synthesis, and structure-activity relationship of new isobenzofuranone ligands of protein kinase C., Bioorganic & Medicinal Chemistry Letters, Vol.14, No.11, 2963-2967, 2004.
(要約)
Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. We have designed novel PKC ligands having an isobenzofuranone template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with the PKCdelta C1B ligand-binding domain. Several isobenzofuranone derivatives were synthesized and their PKCalpha binding activities were evaluated. The pivaloyl derivative 1f was found to be a strong PKCalpha ligand, and the structure-activity relationship is well explained by our proposed binding model.
(キーワード)
Benzofurans / Binding Sites / Dose-Response Relationship, Drug / Drug Design / Enzyme Inhibitors / Humans / Hydrogen Bonding / Ligands / Molecular Structure / Protein Binding / Protein Kinase C / 構造活性相関 (structureactivity relationship)