Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H23N3O5 |
Molecular Weight | 397.4244 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN(C)CC1=C(OC2=CC=CC=C12)C(=O)NCCOC3=CC=C(C=C3)C(=O)NO
InChI
InChIKey=MAUCONCHVWBMHK-UHFFFAOYSA-N
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)
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/25520806Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16731764
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25520806
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16731764
Abexinostat (PCI-24781) is a novel, second-generation phenyl hydroxamic acid–based, orally bioavailable HDAC inhibitor that has previously been shown to have activity in vitro and in vivo against a broad array of cancers, including hematopoietic malignancies and bone and soft-tissue sarcomas. Abexinostat is a pan-HDAC inhibitor mostly targeting HDAC1 with Ki of 7 nM, modest potent to HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Abexinostat exhibits potent antitumor activity against a variety of tumor cell lines with GI50 ranging from 0.15 uM to 3.09 uM. PCI-24781 also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 uM. Abexinostat treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX. It has also shown good tolerability and activity in Phase I and II clinical trials against lymphoma, as well as against solid tumors in Phase-I trials. Additionally, it acts as a potent radiosensitizing agent and is synergistic with cytotoxic chemotherapy, such as doxorubicin in preclinical models.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16731764 |
7.0 nM [Ki] | ||
Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16731764 |
8.2 nM [Ki] | ||
Target ID: CHEMBL1865 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16731764 |
17.0 nM [Ki] | ||
Target ID: CHEMBL1937 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16731764 |
19.0 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00724984
Dose Escalation: Up to 5 cohorts will receive Abexinostat (PCI-24781) orally at doses starting at 30mg/m2 two times a day approximately 4-6 hours apart ("BID"), up to 90mg/m2 administered 5 days/week during the first 21 days of each 28 day cycle until the maximum tolerated dose (MTD) is reached. If a dose limiting toxicity (DLT) occurs, then the next cohort will receive Abexinostat (PCI-24781) BID for 7 days every other week (2 times in a 28 day cycle).
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16731764
inhibited pure recombinant HDAC1 with a K(i) of 0.007 umol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range.
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NCI_THESAURUS |
C1946
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DB12565
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11749858
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C68920
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ABEXINOSTAT
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CHEMBL2103863
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)