| Stereochemistry | ABSOLUTE |
| Molecular Formula | C25H22ClN5O2S.2H2O |
| Molecular Weight | 528.023 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O.O.CC1=NN=C2[C@H](CC(=O)NC3=CC=C(O)C=C3)N=C(C4=C(SC(C)=C4C)N12)C5=CC=C(Cl)C=C5
InChI
InChIKey=LZLFEVJSMKCZGE-FJSYBICCSA-N
InChI=1S/C25H22ClN5O2S.2H2O/c1-13-14(2)34-25-22(13)23(16-4-6-17(26)7-5-16)28-20(24-30-29-15(3)31(24)25)12-21(33)27-18-8-10-19(32)11-9-18;;/h4-11,20,32H,12H2,1-3H3,(H,27,33);2*1H2/t20-;;/m0../s1
The BET-bromodomain inhibitor OTX015 (MK-8628) was initially developed by Mitsubishi Tanabe Pharma Corporation, but then was licensed by OncoEthix, privately held biotechnology company. OTX015 is a selective bromodomains: BRD2, BRD3, and BRD4 inhibitor and inhibits their binding to AcH4. Bromodomains have an important role in the targeting of chromatin-modifying enzymes to specific sites, including methyltransferases, HATs and transcription factors and regulate diverse biological processes from cell proliferation and differentiation to energy homeostasis and neurological processes. OTX015 has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models. Oral administration of OTX-015 markedly inhibited tumor growth and reduced tumor volume. OTX015 is currently in Phase 1b studies for the treatment of hematological malignancies and advanced solid tumors such as Triple Negative Breast Cancer, Non-small Cell Lung Cancer, Castrate-resistant Prostate Cancer (CRPC) and Pancreatic Ductal Adenocarcinoma. In addition, OTX015 was in phase II for the treatment of Glioblastoma Multiforme, but there were not detected clinical activity of the drug in the treatment populations and trial was closed.
CNS Activity
Originator
Approval Year
Doses
AEs
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
Drug as victim
PubMed
Sample Use Guides
OTX105/MK-8628 10, 20 and/or 40 mg capsules. Participants receive OTX105/MK-8628 capsules once daily in a fasted state in the morning on days 1-21 of each 21-day cycle. Starting dose for dose escalation is 80 mg.
Route of Administration:
Oral
Cellular effects of OTX015 in various acute leukemia subtypes were evaluated. Cell viability after OTX015 exposure was assessed with the MTT assay in nine AML (Acute myeloid leukemias) and four ALL (Acute lymphoid leukemias) cell lines. Significant growth inhibition, defined as a submicromolar IC50, was found in six of nine AML cell lines and all four ALL cell lines. The K562 and KG1a AML cell lines were resistant to OTX015. The effect of 500 nM OTX015 exposure for 48h on the cell cycle resulted in decreased transition from G1 to S-phase in all 13 cell lines and a significant increase in cells in the sub-G1 phase in KG1a, KG1, HEL, KASUMI and JURKAT cell lines. Treatment with OTX015 at doses from 25 to 500 nM for 72h induced significant apoptosis, as detected by Annexin V staining and PI uptake. At 500 nM OTX015, 30-90% of cells were apoptotic in five of nine AML cell lines (HEL, NB4, NOMO-1, OCI-AML3, KASUMI) and 50-90% in two of four ALL cell lines. Finally, 72h exposure to 500 nM OTX015 induced mitochondrial apoptosis by cytochrome c release and caspase-3 activation
ACTIVE MOIETY
SUBSTANCE RECORD
