2. Academic Validation
  3. Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic

Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic

  • J Med Chem. 2013 Feb 14;56(3):1228-46. doi: 10.1021/jm301674z.
Kentaro Hashimoto 1,  Bunnai Saito,  Naoki Miyamoto,  Yuya Oguro,  Daisuke Tomita,  Zenyu Shiokawa,  Moriteru Asano,  Hiroyuki Kakei,  Naohiro Taya,  Masanori Kawasaki,  Hiroyuki Sumi,  Masato Yabuki,  Kenichi Iwai,  Sei Yoshida,  Mie Yoshimatsu,  Kazunobu Aoyama,  Yohei Kosugi,  Takashi Kojima,  Nao Morishita,  Douglas R Dougan,  Gyorgy P Snell,  Shinichi Imamura,  Tomoyasu Ishikawa
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 23298277 DOI: 10.1021/jm301674z
Abstract

To develop novel inhibitor of Apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of Caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast Cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100682
    cIAP1/XIAP抑制剂
    IAP
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