BIRABRESIB DIHYDRATE

Details

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

Structure Search

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

HIDE SMILES / InChI

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C25H22ClN5O2S
Molecular Weight	491.992
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.merck.com/licensing/our-partnership/oncoethix-press-release.html | https://www.ncbi.nlm.nih.gov/pubmed/25989842 | http://meetinglibrary.asco.org/content/169627-176

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

Targets

Primary Target	Pharmacology	Condition	Potency
Bromodomain-containing protein 4 13 Target ID: CHEMBL3085619 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25989842	Inhibitor 8297
Bromodomain-containing protein 3 7 Target ID: CHEMBL1795186 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25989842	Inhibitor 8297
Bromodomain-containing protein 2 7 Target ID: CHEMBL1293289 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25989842	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Hematologic malignancies 19 Sources: http://www.merck.com/licensing/our-partnership/oncoethix-press-release.html	Primary	Phase I 428	Unknown Approved Use Unknown
Glioblastoma multiforme 30 Sources: http://meetinglibrary.asco.org/content/169627-176	Primary	Phase II 1132	Unknown Approved Use Unknown
Triple-negative breast cancer 12 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27935867	Primary	Phase I 428	Unknown Approved Use Unknown
Castrate-resistant prostate cancer 20 Sources: https://clinicaltrials.gov/show/NCT02259114	Primary	Phase I 428	Unknown Approved Use Unknown
Pancreatic ductal adenocarcinoma 14 Sources: https://clinicaltrials.gov/show/NCT02259114	Primary	Phase I 428	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/show/NCT02259114	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1292 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26341814	160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered:		BIRABRESIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2627 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27063977	160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered:		BIRABRESIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
13921 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26341814	160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered:		BIRABRESIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
14090 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27063977	160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered:		BIRABRESIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
5.48 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26341814	160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered:		BIRABRESIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
120 mg 1 times / day multiple, oral Studied dose Dose: 120 mg, 1 times / day Route: oral Route: multiple Dose: 120 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Thrombocytopenia, Mucositis... Dose limiting toxicities: Thrombocytopenia (grade 4, 33.3%) Mucositis (grade 2, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5
120 mg 1 times / day multiple, oral Studied dose Dose: 120 mg, 1 times / day Route: oral Route: multiple Dose: 120 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Impaired taste, Thrombocytopenia... Dose limiting toxicities: Impaired taste (grade 2, 25%) Thrombocytopenia (grade 4, 25%) Fatigue (grade 2, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5
120 mg 1 times / day multiple, oral Studied dose Dose: 120 mg, 1 times / day Route: oral Route: multiple Dose: 120 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Fatigue, Thrombocytopenia... Dose limiting toxicities: Fatigue (grade 3, 20%) Thrombocytopenia (grade 3, 20%) Vomiting (grade 3, 20%) Diarrhoea (grade 3, 40%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5
120 mg 1 times / day multiple, oral Studied dose Dose: 120 mg, 1 times / day Route: oral Route: multiple Dose: 120 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 33.3%) Neutropenia (grade 4, 16.7%) Hyponatraemia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5
160 mg 1 times / day multiple, oral Studied dose Dose: 160 mg, 1 times / day Route: oral Route: multiple Dose: 160 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063977 Page: p.4	unhealthy, ADULT n = 5 Health Status: unhealthy Condition: acute leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/27063977 Page: p.4	DLT: Fatigue, Diarrhoea... Dose limiting toxicities: Fatigue (grade 3, 20%) Diarrhoea (grade 3, 20%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063977 Page: p.4
40 mg 2 times / day multiple, oral Studied dose Dose: 40 mg, 2 times / day Route: oral Route: multiple Dose: 40 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Thrombocytopenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 83%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5
80 mg 1 times / day multiple, oral Studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5	DLT: Thrombocytopenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 28.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/27063978 Page: p.5

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737	substrate 1037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP2 383 P-gp 1461 BSEP 402 OATP1B3 706 CYP2A6 707 OATP1B1 788 MRP3 157 UGT1A1 204	UGT1A10 291 UGT1A9 380 UGT1A7 236 UGT1A3 422 P-gp 1537 UGT1A1 418 CYP2C19 991 UGT1A8 283

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677791	inconclusive [IC50 3.475 uM]
MRP2 475	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	no
MRP3 207	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	no
UGT1A1 254	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	weak [IC50 10 uM]
BSEP 403	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	weak [IC50 >10 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	weak [IC50 >5 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/76/NCT02698176/Prot_SAP_000.pdf#page=24 Page: 24.0	yes [IC50 3 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	yes [IC50 >10 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	yes [IC50 >10 uM]

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	likely
CYP3A4 1737	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	major
UGT1A7 236	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	major
CYP2C9 1037	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
UGT1A1 418	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
UGT1A10 291	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
UGT1A3 422	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
UGT1A8 283	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
UGT1A9 380	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=19 Page: 19.0	minor
P-gp 1537	substrate 3367 Sources: https://www.clinicaltrials.gov/ProvidedDocs/89/NCT02698189/Prot_SAP_000.pdf#page=20 Page: 20.0	yes

PubMed

Title	Date	PubMed
Targeting epigenetic readers in cancer.	2012 Nov 1	23113498
Compendium of aberrant DNA methylation and histone modifications in cancer.	2014 Dec 5	25194808
Targeting bromodomains: epigenetic readers of lysine acetylation.	2014 May	24751816
The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs.	2015 Apr 1	25623213
BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells.	2015 Jul 10	25989842
OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.	2016 Nov 1	27388964
Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.	2016 Sep 8	27607580
The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus.	2017 Jan 31	27935867

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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

Substance Class	Chemical Created by `admin` on `Fri Dec 15 17:39:30 GMT 2023` Edited by `admin` on `Fri Dec 15 17:39:30 GMT 2023`
Record UNII	4Q356KA5V2
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BIRABRESIB DIHYDRATE

Common Name

English

OTX015 DIHYDRATE

Code

English

OTX-015 DIHYDRATE

Code

English

6H-THIENO(3,2-F)(1,2,4)TRIAZOLO(4,3-A)(1,4)DIAZEPINE-6-ACETAMIDE, 4-(4-CHLOROPHENYL)-N-(4-HYDROXYPHENYL)-2,3,9-TRIMETHYL-, HYDRATE (1:2), (6S)-

Systematic Name

English

MK-8628 DIHYDRATE

Code

English

Y-803

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

433914