Delving into the Latest Updates on Birabresib dihydrate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Birabresib (USAN/INN)

+ [4]

Target

BRD2 x BRD3 x BRD4

Mechanism

BRD2 inhibitors(Bromodomain-containing protein 2 inhibitors), BRD3 inhibitors(Bromodomain-containing protein 3 inhibitors), BRD4 inhibitors(Bromodomain-containing protein 4 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesHemic and Lymphatic Diseases+ [8]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaAdvanced Malignant Solid Neoplasm+ [13]

Originator Organization

Mitsubishi Tanabe Pharma Corp.

Active Organization-

Inactive Organization

Oncoethix GmbH

Merck Sharp & Dohme Corp.

Mitsubishi Tanabe Pharma Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC25H26ClN5O4S

InChIKeyLZLFEVJSMKCZGE-FJSYBICCSA-N

CAS Registry204587-26-8

View All Structures (2)

This is a study to determine the recommended dose of birabresib (MK-8628) for further studies in participants with acute myeloid leukemia (AML) including AML de novo and AML secondary to myelodysplastic syndrome (MDS) and in participants with diffuse large B cell lymphoma (DLBCL). The recommended dose will be established by evaluating dose limiting toxicity (DLT), safety, tolerability, and early efficacy signals.

Start Date19 May 2016

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT02698176 / TerminatedPhase 1

A Phase IB Dose Exploration Trial With MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects With Selected Advanced Solid Tumors

This is a study to determine the recommended dose of birabresib (MK-8628)(formerly known as OTX015) for further studies in participants with advanced nuclear protein in testis (NUT) midline carcinoma (NMC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), or castration-resistant prostate cancer (CRPC). This is a two-part parallel study: Part A will establish the recommended dose by evaluating dose limiting toxicity (DLT), safety, discontinuation, and early efficacy and Part B will enroll participants with NMC only and will evaluate safety and efficacy in this population.

Start Date04 May 2016

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT02303782 / WithdrawnPhase 1/2

A Phase Ib/II Study Assessing the BET-bromodomain (BRD) Inhibitor OTX015 in Combination With Azacitidine (AZA) or AZA Single Agent in Patients With Newly-diagnosed Acute Myeloid Leukemia (AML) Not Candidate for Standard Intensive Induction Therapy (SIIT)

This study is designed in its first part (phase Ib) to determine the recommended dose of the OTX015 + Vidaza (azacitidine) combination in newly diagnosed acute myeloid leukemia patients not candidate for standard intensive induction therapy.
It will be followed by a randomized phase II part to assess the efficacy of the combination using 2 arms : Vidaza (azacitidine) alone vs. OTX015 in combination with Vidaza (azacitidine).

Start Date01 Jan 2015

Sponsor / Collaborator

Oncoethix GmbH

100 Clinical Results associated with Birabresib dihydrate

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100 Translational Medicine associated with Birabresib dihydrate

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100 Patents (Medical) associated with Birabresib dihydrate

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92

Literatures (Medical) associated with Birabresib dihydrate

20 May 2024·Cancer Research Communications

Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer

Article

Author: Kawata, Naomi ; Mashima, Tetsuo ; Lee, Jin ; Seimiya, Hiroyuki ; Morino, Shun ; Nakamura, Ayane ; Takeuchi, Kengo ; Wakatsuki, Takeru ; Inaba, Saori ; Kumagai, Koshi ; Yamamoto, Noriko ; Yamaguchi, Kensei

AbstractAnticancer drug-tolerant persister (DTP) cells at an early phase of chemotherapy reshape refractory tumors. Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is commonly upregulated by various anticancer drugs in gastric cancer patient-derived cells (PDC) and promotes tumor growth. However, the mechanism underlying the generation of ALDH1A3-positive DTP cells remains elusive. Here, we investigated the mechanism of ALDH1A3 expression and a combination therapy targeting gastric cancer DTP cells. We found that gastric cancer tissues treated with neoadjuvant chemotherapy showed high ALDH1A3 expression. Chromatin immunoprecipitation (ChIP)-PCR and ChIP sequencing analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the bromodomain and extraterminal (BET) inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth. In DTP cells, BRD4, but not BRD2/3, was recruited to the ALDH1A3 promoter and BRD4 knockdown decreased drug-induced ALDH1A3 upregulation. Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell–targeting agents for gastric cancer treatment.Significance:Drug resistance hampers the cure of patients with cancer. To prevent stable drug resistance, DTP cancer cells are rational therapeutic targets that emerge during the early phase of chemotherapy. This study proposes that the epigenetic regulation by BET inhibitors may be a rational therapeutic strategy to eliminate DTP cells.

01 Feb 2024·European Journal of Medicinal Chemistry

DW71177: A novel [1,2,4]triazolo[4,3-a]quinoxaline-based potent and BD1-Selective BET inhibitor for the treatment of acute myeloid leukemia

Article

Author: Lim, Jae Kyung ; Ali, Imran ; Roe, Jae-Seok ; Youm, Jihyun ; Chae, Chong Hak ; Park, Whui Jung ; Hwang, Yun-Ha ; Cha, Hyung Jin ; Lee, Kwangho ; Lim, Byungho ; Jeong, Docgyun ; Lee, Sang Ho ; Woo, Jae-Sung ; Choi, Gildon ; Kim, Jung Hwan

The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (K_ac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined K_ac-binding pockets. Here, we present DW-71177, a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the K_ac-binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia.

01 Oct 2023·International Journal of Radiation Oncology*Biology*Physics

Combination of BET Inhibition with Radiation Induces Anti-Tumor Immune Response in Pre-Clinical Models of ER-Positive Breast Cancer

Article

Author: Alluri, P G ; Rahimi, A S ; Vidal, C ; Arbab, M

PURPOSE/OBJECTIVE(S)Despite advances in multidisciplinary care, the risk of late recurrence in Estrogen Receptor-positive (ER+) breast cancer (BC) patients following standard-of-care treatment ranges from 20-52% at 20 years. While immune checkpoint inhibitors (CPI), have shown enormous potential in inducing long term remission in some cases, patients with ER+ BC show poor response to these agents. The objective of this study is to develop effective radiation therapy (RT)-based combination regimens that induce anti-tumor immunity against immunologically cold ER+ breast tumors.BACKGROUNDWe have previously shown that pharmacological inhibition of bromodomain and extraterminal domain (BET) family of epigenetic regulator proteins overcomes both endocrine therapy resistance and radiation resistance in pre-clinical models of ER+ BC by reversing pathological reprogramming of transcriptional and DNA repair pathways, respectively. In this study, we explore the potential of RT+BET inhibition combination to elicit anti-tumor immunity against ER+ BC.MATERIALS/METHODSA unique ER+ BC model, MXT+, was used to generate tumors in female, BDF1 mice. PD-L1 expression following RT or RT+OTX015 (a BET inhibitor) was assessed by Western blot analysis. Comet assay was used to assess the degree of unrepaired DNA damage following treatment with RT alone, OTX015 alone and RT+OTX015. Multiplex IHC was used to assess changes in tumor microenvironment after various treatments. Tumor growth characteristics were established following treatment with vehicle, RT alone (8 Gy x 3), OTX015 alone (100 mg/kg x 3 days) and RT+OTX015.RESULTSUsing murine ER+ BC model, MXT+, we show that RT is a potent inducer of PD-L1 expression. Combination of RT+OTX015 completely ablated RT-mediated PD-L1 induction at the transcription level. OTX015 also accentuated RT-induced DNA damage through inhibition of NHEJ pathway, resulting in increased micronuclei formation (which activate cGAS/STING pathway, a critical bridge between innate and adaptive immunity). Combination of OTX015 with RT also caused a statistically significant (on unpaired t test) increase tumor infiltrating lymphocytes. In in vivo therapeutic studies, combination of OTX015 with RT (8 Gy x 3) resulted in extraordinary synergy and caused complete inhibition of long-term tumor growth. Treatment with RT alone (8 Gy x 3) or OTX015 alone (on 3 consecutive days) only caused modest inhibition of tumor growth. ANOVA with Dunnett's test was used to adjust for multiple comparisons and showed statistically significant difference in tumor growth between OTX015+RT arm and OTX alone as well as OTX015+RT arm and RT alone.CONCLUSIONPatients with ER+ BC face high risk of late recurrence after definitive treatment and show poor response to immune CPIs. We show that combination of BET inhibition with RT induces anti-tumor immunity and completely prevents tumor growth. Clinical validation of this regimen is warranted to prevent late recurrences in ER+ BC patients.

100 Deals associated with Birabresib dihydrate

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External Link

KEGG	Wiki	ATC	Drug Bank
D10911	Birabresib dihydrate	-	DB15189

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	-	Oncoethix GmbH	01 Jan 2015
Glioblastoma Multiforme	Phase 2	-	Oncoethix GmbH	29 Oct 2014
ALK positive Non-Small Cell Lung Cancer	Phase 2	-	Oncoethix GmbH	23 Oct 2014
Castration-Resistant Prostatic Cancer	Phase 2	-	Oncoethix GmbH	23 Oct 2014
KRAS mutant Non-small Cell Lung Cancer	Phase 2	-	Oncoethix GmbH	23 Oct 2014
NUT midline carcinoma	Phase 2	-	Oncoethix GmbH	23 Oct 2014
Pancreatic Ductal Adenocarcinoma	Phase 2	-	Oncoethix GmbH	23 Oct 2014
Acute Lymphoblastic Leukemia	Phase 2	-	Oncoethix GmbH	14 Dec 2012
Multiple Myeloma	Phase 2	-	Oncoethix GmbH	14 Dec 2012
Hematologic Neoplasms	Phase 2	US	Mitsubishi Tanabe Pharma Corp.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02698189 (8628-005 \| MK-8628-005, CTgov)	Phase 1	Acute Myeloid Leukemia \| Diffuse Large B-Cell Lymphoma	9	MK-8628 (MK-8628 20 mg AML Cohort)	ijovnqmhrk(hbhmpxfjqk) = hjbiekywxt crfhfgvbvb (ztfyvduvgp, zlktelpabz - bqvfgugbgm) View more	-	23 Jul 2019
				MK-8628 (MK-8628 20 mg DLBCL Cohort)	ijovnqmhrk(hbhmpxfjqk) = fjywkyckpb crfhfgvbvb (ztfyvduvgp, bezlfrlvpl - hdnkzgogmp) View more
NCT02259114 (CTgov)	Phase 1	KRAS mutant Non-small Cell Lung Cancer \| Pancreatic Ductal Adenocarcinoma \| Advanced Malignant Solid Neoplasm \| Triple Negative Breast Cancer \| Castration-Resistant Prostatic Cancer \| NUT midline carcinoma \| ALK positive Non-Small Cell Lung Cancer	47	MK-8628 (MK-8628 Continuous Dosing Regimen 80 mg/Day)	dmevtcwbmz(qnqsguhkaw) = spgzmbpnyx qocwjwnysv (aqoazxlenh, cnjtcgqcgd - yndufjskrm) View more	-	01 Oct 2018
				MK-8628 (MK-8628 Continuous Dosing Regimen 100 mg/Day)	dmevtcwbmz(qnqsguhkaw) = fdjcjwcewz qocwjwnysv (aqoazxlenh, fetwpeixdy - xpoqgwpadh) View more
NCT02296476 (8628-002 \| MK-8628-002, CTgov)	Phase 2	Glioblastoma Multiforme	12	MK-8628 (MK-8628 80 mg)	olfvbbcqps(ahefjeetbt) = tulkzizebj qiimrjfbuh (ahwhccszvx, dfyloxbjuv - kmhpyhggyu) View more	-	17 May 2018
				MK-8628 (MK-8628 120 mg)	olfvbbcqps(ahefjeetbt) = aenzposjxp qiimrjfbuh (ahwhccszvx, kzlejricbw - etjjhqpjwi) View more
AACR2017	Phase 2	Neuroblastoma	-	JQ1	gijwwtxdlw(rexiitgkbh) = vdovnxpwup qnnzcqcgrb (sbkpfsqpzj )	Positive	01 Jul 2017
				OTX-015	gijwwtxdlw(rexiitgkbh) = kpyyjcauxo qnnzcqcgrb (sbkpfsqpzj )
NCT02259114 (Pubmed)	Phase 1	Triple Negative Breast Cancer	47	OTX015	gmzabiuqql(btzqudyahu) = cfdqfrfanb qcduhshmsc (mkcetfbrqh )	-	31 Jan 2017
NCT02296476 (8628-002 \| MK-8628-002, ASCO2016)	Phase 2	Recurrent Glioblastoma	12	MK-8628 80 mg QD	lbgjjjiwtf(lavidliwga) = 3 pts had dose-limiting toxicity: 1 at DL1 (grade [G] 3 thrombocytopenia > 7 days) and 2 at DL3 (G3 thrombocytopenia > 7 days without bleeding; G3 hyperbilirubinemia lasting 2 days) fuencmrqfv (xzovrbphsj ) View more	Negative	20 May 2016
				MK-8628 120 mg QD
NCT01713582 (Pubmed \| Lancet Haematol) Manual	Phase 1	Multiple Myeloma \| Lymphoma	45	OTX015	(lwcgxjuezs) = 80 mg once a day: no DLTs; 40 mg twice a day: five patients nvvcowatvc (jzlhfnlndf ) View more	Positive	01 Apr 2016
NCT01713582 (Pubmed \| Lancet Haematol) Manual	Phase 1	acute leukemia Third line	41	OTX015	(rxxkmmmapx) = No DLT was recorded until 160 mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120 mg doses hampered patient compliance zblyljthbu (xknlpkbtjz ) View more	Positive	01 Apr 2016
NCT01713582 (271 THE BET BROMODOMAIN INHIBITOR OTX015, ICML2015)	Phase 1	Lymphoma miR-92a-1-5p \| miR-21-3p \| miR-96-5p ... View more	-	OTX015 (MK-8628)	mrgixlnppx(hvgkzzafyq) = kcwtztqumz wejlkfyagx (gxytjpmszt, 0.041)	Positive	09 Jun 2015
AACR2014	Phase 1	Hematologic Neoplasms	36	OTX015	(uncrkhomad) = AUC-dose proportionality was observed uusguqfuhi (heiiwswrxi )	-	01 Oct 2014