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

Hashimoto K, Saito B, Miyamoto N, Oguro Y, Tomita D, Shiokawa Z, Asano M, Kakei H, Taya N, Kawasaki M, Sumi H, Yabuki M, Iwai K, Yoshida S, Yoshimatsu M, Aoyama K, Kosugi Y, Kojima T, Morishita N, Dougan DR, Snell GP, Imamura S, Ishikawa T
J Med Chem 56 1228-46 (2013)
Related entries: 4hy4, 4hy5

Cited: 17 times
EuropePMC logo PMID: 23298277

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).

Articles - 4hy0 mentioned but not cited (2)

  1. Molecular modeling in the age of clinical genomics, the enterprise of the next generation. Prokop JW, Lazar J, Crapitto G, Smith DC, Worthey EA, Jacob HJ. J Mol Model 23 75 (2017)
  2. An Intriguing Correlation Based on the Superimposition of Residue Pairs with Inhibitors that Target Protein-Protein Interfaces. Nakadai M, Tomida S, Sekimizu K. Sci Rep 6 18543 (2016)


Reviews citing this publication (1)

  1. Synthesis of complex unnatural fluorine-containing amino acids. Brittain WDG, Lloyd CM, Cobb SL. J Fluor Chem 239 109630 (2020)

Articles citing this publication (14)

  1. Covalent Inhibitors of Protein-Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues. Gambini L, Baggio C, Udompholkul P, Jossart J, Salem AF, Perry JJP, Pellecchia M. J Med Chem 62 5616-5627 (2019)
  2. Potent and selective small-molecule inhibitors of cIAP1/2 proteins reveal that the binding of Smac mimetics to XIAP BIR3 is not required for their effective induction of cell death in tumor cells. Sun H, Lu J, Liu L, Yang CY, Wang S. ACS Chem Biol 9 994-1002 (2014)
  3. Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach. Baggio C, Gambini L, Udompholkul P, Salem AF, Aronson A, Dona A, Troadec E, Pichiorri F, Pellecchia M. J Med Chem 61 6350-6363 (2018)
  4. Aryl-fluorosulfate-based Lysine Covalent Pan-Inhibitors of Apoptosis Protein (IAP) Antagonists with Cellular Efficacy. Baggio C, Udompholkul P, Gambini L, Salem AF, Jossart J, Perry JJP, Pellecchia M. J Med Chem 62 9188-9200 (2019)
  5. Comparative Anticancer Potentials of Taxifolin and Quercetin Methylated Derivatives against HCT-116 Cell Lines: Effects of O-Methylation on Taxifolin and Quercetin as Preliminary Natural Leads. Mohammed HA, Almahmoud SA, El-Ghaly EM, Khan FA, Emwas AH, Jaremko M, Almulhim F, Khan RA, Ragab EA. ACS Omega 7 46629-46639 (2022)
  6. Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists. Asano M, Hashimoto K, Saito B, Shiokawa Z, Sumi H, Yabuki M, Yoshimatsu M, Aoyama K, Hamada T, Morishita N, Dougan DR, Mol CD, Yoshida S, Ishikawa T. Bioorg Med Chem 21 5725-5737 (2013)
  7. Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method. Lim H, Jin X, Kim J, Hwang S, Shin KB, Choi J, Nam KY, No KT. Comput Struct Biotechnol J 17 1217-1225 (2019)
  8. Stability and Cell Permeability of Sulfonyl Fluorides in the Design of Lys-Covalent Antagonists of Protein-Protein Interactions. Gambini L, Udompholkul P, Salem AF, Baggio C, Pellecchia M. ChemMedChem 15 2176-2184 (2020)
  9. Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells. Shiokawa Z, Hashimoto K, Saito B, Oguro Y, Sumi H, Yabuki M, Yoshimatsu M, Kosugi Y, Debori Y, Morishita N, Dougan DR, Snell GP, Yoshida S, Ishikawa T. Bioorg Med Chem 21 7938-7954 (2013)
  10. LiAlH4 -Induced Selective Ring Rearrangement of 2-(2-Cyanoethyl)aziridines toward 2-(Aminomethyl)pyrrolidines and 3-Aminopiperidines as Eligible Heterocyclic Building Blocks. Dolfen J, Vervisch K, De Kimpe N, D'hooghe M. Chemistry 22 4945-4951 (2016)
  11. Organocatalytic synthesis of optically active β-branched α-amino esters via asymmetric biomimetic transamination. Su C, Xie Y, Pan H, Liu M, Tian H, Shi Y. Org Biomol Chem 12 5856-5860 (2014)
  12. Impact of P-Glycoprotein on Intestinal Absorption of an Inhibitor of Apoptosis Protein Antagonist in Rats: Mechanisms of Nonlinear Pharmacokinetics and Food Effects. Yamamoto S, Kosugi Y, Hirabayashi H, Moriwaki T. Pharm Res 35 190 (2018)
  13. Characterization of a Potent and Orally Bioavailable Lys-Covalent Inhibitor of Apoptosis Protein (IAP) Antagonist. Udompholkul P, Garza-Granados A, Alboreggia G, Baggio C, McGuire J, Pegan SD, Pellecchia M. J Med Chem 66 8159-8169 (2023)
  14. Construction of 5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles via the One-Pot Reaction of Alkyl Isocyanides with Aryl/Alkyl Carbonyl Chlorides and Diaminomaleonitrile: Fluorescence and Antimicrobial Activity Evaluation. Al-Azmi A, John E. Molecules 27 8278 (2022)


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