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Abexinostat

Abexinostat
Names
IUPAC name
3-[(Dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide
Other names
PCI-24781; CRA-024781
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.241.399 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C21H23N3O5/c1-24(2)13-17-16-5-3-4-6-18(16)29-19(17)21(26)22-11-12-28-15-9-7-14(8-10-15)20(25)23-27/h3-10,27H,11-13H2,1-2H3,(H,22,26)(H,23,25) checkY
    Key: MAUCONCHVWBMHK-UHFFFAOYSA-N checkY
  • InChI=1/C21H23N3O5/c1-24(2)13-17-16-5-3-4-6-18(16)29-19(17)21(26)22-11-12-28-15-9-7-14(8-10-15)20(25)23-27/h3-10,27H,11-13H2,1-2H3,(H,22,26)(H,23,25)
    Key: MAUCONCHVWBMHK-UHFFFAOYAM
  • O=C(NO)c3ccc(OCCNC(=O)c2oc1ccccc1c2CN(C)C)cc3
Properties
C21H23N3O5
Molar mass 397.431 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Abexinostat (INN,[1] formerly PCI-24781) is an experimental drug candidate for cancer treatment.[2] It was developed by Pharmacyclics and licensed to Xynomic. As of 2013, it was in Phase II clinical trials for B-cell lymphoma.[3][needs update] Pre-clinical study suggests the potential for treatment of different types of cancer as well.[4][5][6][7]

Abexinostat exerts its effect as a pan-histone deacetylase inhibitor[8][9] and inhibits RAD51, which is involved in repairing DNA double strand breaks.[10]

Progress

Abexinostat has been granted a fast track designation by the FDA for the treatment of patients with relapsed or refractory follicular lymphoma in the fourth-line setting. This designation is significant as it aims to expedite the development and review of drugs intended to treat serious conditions and fill an unmet medical need.

Research

The FORERUNNER conducted a study, a potentially pivotal phase II trial of abexinostat monotherapy in patients with relapsed/refractory follicular lymphoma, in the United States and Europe.[11] In the phase II study, abexinostat showed a modest overall response rate (ORR) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with a notably higher ORR observed in patients with follicular lymphoma. This study involved 100 patients treated with 80 mg of abexinostat twice daily for 14 days of a 21-day cycle. The ORR for follicular lymphoma specifically was 56%, indicating a significant impact on this lymphoma subtype. The study also reported grade ≥3 adverse events in a considerable number of patients, with thrombocytopenia, neutropenia, and anemia being the most frequently reported.[11]

Safety and efficacy

Abexinostat has been characterized by its unique pharmacokinetic profile and oral dosing schedule, allowing for continuous exposure at concentrations required for efficient tumor cell killing. [12]

References

  1. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). 2011.
  2. ^ "Abexinostat". NCI Cancer Dictionary.
  3. ^ "Abexinostat HCl (PCI-24781), PanHDAC-inhibitor". Pharmacyclics. Archived from the original on 2013-10-27.
  4. ^ Bhalla, S; Balasubramanian, S; David, K; Sirisawad, M; Buggy, J; Mauro, L; Prachand, S; Miller, R; Gordon, LI; Evens, AM (2009). "PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells". Clinical Cancer Research. 15 (10): 3354–65. doi:10.1158/1078-0432.CCR-08-2365. PMC 2704489. PMID 19417023.
  5. ^ Lopez, G; Liu, J; Ren, W; Wei, W; Wang, S; Lahat, G; Zhu, QS; Bornmann, WG; McConkey, DJ; Pollock, RE; Lev, DC (2009). "Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma". Clinical Cancer Research. 15 (10): 3472–83. doi:10.1158/1078-0432.CCR-08-2714. PMID 19417021. S2CID 18862692. (Erratum: doi:10.1158/1078-0432.CCR-15-0351, PMID 25833311. If the erratum has been checked and does not affect the cited material, please replace {{erratum|...}} with {{erratum|...|checked=yes}}.)
  6. ^ Rivera-Del Valle, N; Gao, S; Miller, CP; Fulbright, J; Gonzales, C; Sirisawad, M; Steggerda, S; Wheler, J; Balasubramanian, S; Chandra, J (2010). "PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells". International Journal of Cell Biology. 2010: 207420. doi:10.1155/2010/207420. PMC 2817379. PMID 20145726.
  7. ^ Yang, C; Choy, E; Hornicek, FJ; Wood, KB; Schwab, JH; Liu, X; Mankin, H; Duan, Z (2011). "Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells". Cancer Chemotherapy and Pharmacology. 67 (2): 439–46. doi:10.1007/s00280-010-1344-7. PMID 20461381. S2CID 1344662.
  8. ^ Buggy, JJ; Cao, ZA; Bass, KE; Verner, E; Balasubramanian, S; Liu, L; Schultz, BE; Young, PR; Dalrymple, SA (2006). "CRA-024781: A novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo". Molecular Cancer Therapeutics. 5 (5): 1309–17. doi:10.1158/1535-7163.MCT-05-0442. PMID 16731764.
  9. ^ Adimoolam, S; Sirisawad, M; Chen, J; Thiemann, P; Ford, JM; Buggy, JJ (2007). "HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination". Proceedings of the National Academy of Sciences of the United States of America. 104 (49): 19482–7. Bibcode:2007PNAS..10419482A. doi:10.1073/pnas.0707828104. PMC 2148315. PMID 18042714.
  10. ^ "NCI Drug Dictionary". National Cancer Institute.
  11. ^ a b "FDA Grants Fast Track Designation to Abexinostat for Fourth-Line Follicular Lymphoma". Targeted Oncology. 2019-09-23. Retrieved 2024-02-14.
  12. ^ Ribrag, Vincent; Kim, Won Seog; Bouabdallah, Reda; Lim, Soon Thye; Coiffier, Bertrand; Felloussi, Zakia; Kloos, Ioana; Luan, Ying; Graef, Thorsten; Morschhauser, Franck (2015-12-03). "Safety and Efficacy of Abexinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Results of an Ongoing Phase 2 Study". Blood. 126 (23): 256. doi:10.1182/blood.V126.23.256.256. ISSN 0006-4971. Retrieved 2024-02-14.
Quelle: http://en.wikipedia.org/wiki/Abexinostat