AOH1996

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AOH1996
Identifiers
  • N-[2-[2-(3-methoxyphenoxy)anilino]-2-oxoethyl]naphthalene-1-carboxamide
CAS Number
PubChem CID
ChEBI
Chemical and physical data
FormulaC26H22N2O4
Molar mass426.472 g·mol−1
3D model (JSmol)
  • COC1=CC(=CC=C1)OC2=CC=CC=C2NC(=O)CNC(=O)C3=CC=CC4=CC=CC=C43
  • InChI=1S/C26H22N2O4/c1-31-19-10-7-11-20(16-19)32-24-15-5-4-14-23(24)28-25(29)17-27-26(30)22-13-6-9-18-8-2-3-12-21(18)22/h2-16H,17H2,1H3,(H,27,30)(H,28,29)
  • Key:HDMONPHKMIZXDH-UHFFFAOYSA-N

AOH1996 is an experimental anticancer medication which acts as a small molecule inhibitor of proliferating cell nuclear antigen (PCNA) and is in Phase I clinical trials at City of Hope as of August 2023 for the treatment of solid tumors.[1][2][3][4]

AOH1996 was created to target a post-translationally modified isoform of PCNA, termed caPCNA, which is preferentially found in cancer cells. PCNA is crucial in the body for DNA repair, but targeting it is difficult because of its role in healthy cells. By selectively targeting caPCNA, it may be possible to kill cancer cells without affecting healthy tissues.[5] In vitro testing demonstrated that AOH1996 inhibited the growth and induced cell cycle arrest and apoptotic cell death in a wide variety of cancer cell lines, but had no effect on several normal, nonmalignant cell types.[6][7] In mouse and dog animal models, there were no observed side effects or toxicity even at six times the effective dose.[3] It could be used either as a monotherapy (single drug regimen) or in combination with one or more other chemotherapy drugs.

Although the press described it as a "miracle drug" that would cure cancer, some experts have expressed skepticism. Prof Dorothy Bennett, Director of the Molecular and Clinical Sciences Research Institute, St George’s, University of London, critiqued the paper's cancer killing claim as actually a modest slowing of growth.[8]

The substance was named after the initials and the birth year of Anna Olivia Healey, who died of neuroblastoma in 2006. The funds collected by her parents have helped support the development of the chemical compound.[6][9]

References

  1. ^ WO 2017049206, Malkas LH, Horne D, Hickey RJ, Gu L, "PCNA Inhibitors", published 2017-03-23, assigned to City Of Hope 
  2. ^ Wang YC, Kelso AA, Karamafrooz A, Chen YH, Chen WK, Cheng CT, et al. (March 2023). "Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA ubiquitination". Cell Reports. 42 (4): 112296. doi:10.1016/j.celrep.2023.112296. PMC 10517088. PMID 36961817. S2CID 257716614.
  3. ^ a b Gu L, Li M, Li CM, Haratipour P, Lingeman R, Jossart J, et al. (July 2023). "Small molecule targeting of transcription-replication conflict for selective chemotherapy". Cell Chemical Biology. 30 (10): 1235–1247.e6. doi:10.1016/j.chembiol.2023.07.001. PMC 10592352. PMID 37531956.
  4. ^ "AOH1996 for the Treatment of Refractory Solid Tumors". ClinicalTrials.gov. United States National Library of Medicine. 2023-08-18. Retrieved 2023-08-24.
  5. ^ Gu L, Lingeman R, Yakushijin F, Sun E, Cui Q, Chao J, et al. (December 2018). "The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA". Clinical Cancer Research. 24 (23): 6053–6065. doi:10.1158/1078-0432.CCR-18-0592. PMC 6279569. PMID 29967249.
  6. ^ a b Leuthold K (2 August 2023). "Anna (9) starb an Krebs – jetzt ist die Wunderpille nach ihr benannt" [Anna (9) died of cancer - now the miracle pill is named after her] (in German). 20 Minuten. Retrieved 2023-08-03.
  7. ^ "'Cancer-killing pill' that appears to 'annihilate' solid tumours is now being tested on humans". Sky News. August 2, 2023. Retrieved 2023-08-02.
  8. ^ Bennett (2 August 2023). "expert reaction to study on use of small molecule ligand AOH1996 for inhibiting tumour growth in animals". Science Media Center. Retrieved 2023-12-20.
  9. ^ Healey S (21 December 2021). "AOH-1996 Is Here!". ANNA Fund. Retrieved 2023-08-03.

External links


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