(BR-101801) - 药物靶点：PI3Kγ x PI3Kδ_在研适应症：高脂蛋白血症，高血压，慢性淋巴细胞白血病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

4-[[(1S)-1-(4, 8-Dichloro-1-oxo-2-phenyl-3-isoquinolyl) ethyl] amino]-8H- pyrido[2,3-d] pyrimidin-5-one]

靶点

PI3Kγ x PI3Kδ

作用机制

PI3Kγ抑制剂(磷脂酰肌醇-3激酶γ抑制剂)、PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [2]

在研适应症

高脂蛋白血症高血压慢性淋巴细胞白血病+ [6]

非在研适应症

结直肠癌

原研机构

Boryung Corp.

在研机构

Boryung Corp.

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

关联

2

项与 BR-101801 相关的临床试验

NCT05460364 / Completed临床1期

A Randomized, Open-label, Multiple-dose, 6-sequence, 3-treatment, 3-period, Crossover Study to Evaluate the Pharmacokinetic Interaction and Safety Between BR1018-1 and BR1018-2 in Healthy Adult Subjects

The purpose of this study is to evaluate the pharmacokinetic characteristics and compare the safety and tolerability after repeated separate or combined administrations of BR1018-1 and BR1018-2 in healthy adults.

开始日期2022-08-04

申办/合作机构

Boryung Corp.

NCT04018248 / Active, not recruiting临床1期

A Phase I, Open-label, Multi-center, Dose Escalation, and Expansion Study of BR101801 in Adult Patients With Advanced Hematologic Malignancies

This is a Phase I-II, multi-center, open-label, FIH study comprising of 2 study parts (Phase Ia, Phase Ib).
The Phase Ia (dose escalation) part of the study is designed to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended dose for expansion (RP2D) of BR101801 in subjects with relapsed/refractory B cell lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), and peripheral T cell lymphoma (PTCL).
The Phase Ib (dose expansion) part of the study is designed to assess tumor response and safety in specific advanced relapsed/refractory Peripheral T-cell lymphoma(PTCL) at a dose of BR101801 identified in Phase Ia. Once the RP2D has been determined in Phase Ia (dose escalation), Phase Ib (dose expansion) will commence.

开始日期2020-04-21

申办/合作机构

Boryung Corp.

100 项与 BR-101801 相关的临床结果

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100 项与 BR-101801 相关的转化医学

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100 项与 BR-101801 相关的专利（医药）

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15

项与 BR-101801 相关的文献（医药）

2023-04-01·Drug Metabolism and Disposition

Biotransformation of the Novel Myeloperoxidase Inhibitor AZD4831 in Preclinical Species and Humans

Article

作者: Sundell, Johan ; Amilon, Carl ; Weidolf, Lars ; Li, Xue-Qing ; Inghardt, Tord ; Gopaul, V Sashi ; Sandinge, Ann-Sofie ; Westerlund, Kristina ; Antonsson, Thomas ; Ekdahl, Anja ; Jurva, Ulrik ; Leandersson, Carina

We report herein an in-depth analysis of the metabolism of the novel myeloperoxidase inhibitor AZD4831 ((R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one) in animals and human. Quantitative and qualitative metabolite profiling were performed on samples collected from mass balance studies in rats and humans. Exposure of circulating human metabolites with comparable levels in animal species used in safety assessment were also included. Structural characterization of 20 metabolites was performed by liquid chromatography high-resolution mass spectrometry, and quantification was performed by either ¹⁴C analysis using solid phase scintillation counting or accelerator mass spectrometry and, where available, authentication with synthesized metabolite standards. A complete mass balance study in rats is presented, while data from dogs and human are limited to metabolite profiling and characterization. The metabolism of AZD4831 is mainly comprised of reactions at the primary amine nitrogen and the thiourea sulfur, resulting in several conjugated metabolites with or without desulfurization. A carbamoyl glucuronide metabolite of AZD4831 (M7) was the most abundant plasma metabolite in both human healthy volunteers and heart failure patients after single and repeated dose administration of AZD4831, accounting for 75%-80% of the total drug-related exposure. Exposures to M7 and other human circulating metabolites were covered in rats and/or dogs, the two models most frequently used in the toxicology studies, and were also highly abundant in the mouse, the second model other than rat used in carcinogenicity studies. The carbamoyl glucuronide M7 was the main metabolite in rat bile, while a desulfurized and cyclized metabolite (M5) was abundant in rat plasma and excreta. SIGNIFICANCE STATEMENT: The biotransformation of AZD4831, a novel myeloperoxidase inhibitor inhibiting xanthine derivative bearing thiourea and primary aliphatic amine functions, is described. Twenty characterized metabolites demonstrate the involvement of carbamoylation with glucuronidation, desulfurization, and cyclization as main biotransformation reactions. The carbamoyl glucuronide was the main metabolite in human plasma, likely governed by a significant species difference in plasma protein binding for this metabolite, but this and other human plasma metabolites were covered in animals used in the toxicity studies.

2023-01-01·American journal of cancer research

A combination of BR101801 and venetoclax enhances antitumor effect in DLBCL cells via c-Myc/Bcl-2/Mcl-1 triple targeting.

Article

作者: Kim, Bong-Seog ; Shin, Jisoo ; Jeon, Byeongwook ; Lee, Chae-Eun ; Jung, Kyung Hee ; Hong, Soon-Sun ; Kim, Hong Ro ; Choi, Min-Ji ; Son, Mi Kwon ; Cha, Jong-Ho ; Lee, Yun Ji ; Park, Jung Hee

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.

2023-01-01·American journal of cancer research

BR101801 enhances the radiosensitivity of p53-deficient colorectal cancer cells by inducing G2/M arrest, apoptosis, and senescence in a p53-independent manner.

Article

作者: Park, Mijeong ; Ha, Jimin ; Lee, Yuri ; Choi, Sang Hyun ; Jeong, Youn Kyoung ; Kwon, Youngjoo ; Kim, Byoung Soo

Inhibition of DNA-dependent protein kinase (DNA-PK) in the non-homologous end-joining repair pathway reportedly increases the radiation sensitivity of cancer cells. We have recently reported that BR101801, a novel triple inhibitor of PI3K-gamma (γ), delta (δ), and DNA-PK, functions as an efficient sensitizer of radiation-induced DNA damage in various human solid cancer cells and a xenograft mouse model. Given that the p53 tumor suppressor gene plays an important role in radiotherapeutic efficacy, in the current study, we focused on the impact of the p53 status on BR101801-induced radiosensitization using isogenic HCT116 p53^+/+ and HCT116 p53^-/- human colorectal cancer cell lines. In vitro, HCT116 p53^+/+ and HCT116 p53^-/- human colorectal cancer cells were pretreated with 1 μM BR101801 for 24 h before exposure to ionizing radiation (IR), followed by assays to analyze colony formation, DNA damage, cell cycle changes, senescence, autophagy, apoptosis, and DNA damage response-related proteins. Xenograft mouse models were constructed to examine the potential synergistic effects of BR101801 (50 mg/kg, orally administered once daily) and fractionated IR (2 Gy × 3 days) on tumor growth inhibition in vivo. BR101801 inhibited cell proliferation and prolonged DNA damage in both HCT116 p53^+/+ and HCT116 p53^-/- human colorectal cancer cells. Combined treatment with BR101801 and IR robustly induced G2/M phase cell cycle arrest, apoptosis, and cellular senescence in HCT116 p53^-/- cells when compared with treatment with IR alone. Furthermore, BR101801 synergistically inhibited tumor growth in the HCT116 p53^-/- xenograft mouse model. BR101801 enhanced the radiosensitivity of HCT116 human colorectal cancer cells regardless of their p53 status. Moreover, BR101801 exerted robust synergistic effects on IR-induced cell cycle arrest, apoptosis, and tumor growth inhibition, even in radioresistant HCT116 p53^-/- cells. Overall, these findings provide a scientific rationale for combining BR101801 with IR as a new therapeutic strategy to overcome radioresistance induced by p53 deficiency.

100 项与 BR-101801 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性淋巴细胞白血病	临床1期	韩国	Boryung Corp.	2020-04-21
慢性淋巴细胞白血病	临床1期	美国	Boryung Corp.	2020-04-21
弥漫性大B细胞淋巴瘤	临床1期	韩国	Boryung Corp.	2020-04-21
弥漫性大B细胞淋巴瘤	临床1期	美国	Boryung Corp.	2020-04-21
边缘区B细胞淋巴瘤	临床1期	美国	Boryung Corp.	2020-04-21
边缘区B细胞淋巴瘤	临床1期	韩国	Boryung Corp.	2020-04-21
外周T细胞淋巴瘤	临床1期	美国	Boryung Corp.	2020-04-21
外周T细胞淋巴瘤	临床1期	韩国	Boryung Corp.	2020-04-21
巨球蛋白血症	临床1期	韩国	Boryung Corp.	2020-04-21
巨球蛋白血症	临床1期	美国	Boryung Corp.	2020-04-21

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临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


BR101801 (AACR2020)	N/A	肿瘤	-	BR101801	構壓繭顧築網醖齋壓夢(鑰淵築蓋積選顧構繭積) = 製築遞窪蓋醖製蓋膚襯齋艱範願簾築遞襯夢衊 (繭餘齋憲製壓製淵襯觸 )	积极	2020-08-15
NCT04018248 (ASH2023)	临床1期	外周T细胞淋巴瘤	26	BR101801	(淵鬱窪衊鑰憲遞觸壓糧) = 壓觸壓築築積願衊願構觸製衊鹽糧製遞艱範觸 (獵選築鏇蓋蓋選遞窪顧, 24.5 ~ 71.1) 更多	积极	2023-12-09
NCT04018248 (ASCO2023) 人工标引	临床1期	血液肿瘤	12	BR101801	(築醖憲衊構齋糧廠夢觸) = 齋選糧膚齋願構鏇簾範廠鹽壓膚遞廠襯蓋鏇網 (願糧願襯鹹觸築壓蓋醖 ) 更多	积极	2023-05-31
BR101801 (AACR2020)	N/A	非霍奇金淋巴瘤	-	BR101801	鹽願遞觸觸壓觸鏇憲願(鏇膚鏇鹽艱鑰夢願艱艱) = 夢觸醖顧醖選餘鏇鹽願繭顧簾餘選衊鹹膚餘願 (鬱願築鏇願憲顧鏇鑰願 ) 更多	-	2020-08-15
BR101801 (AACR2020)	N/A	非霍奇金淋巴瘤	-	Venetoclax	製選獵簾遞壓餘繭顧蓋(簾願淵夢網夢艱鬱壓襯) = 願餘遞積選獵壓鹹糧築簾簾壓鏇選蓋襯鹽觸鹽 (製廠艱觸齋鑰製蓋衊餘 )	-	2020-08-15
BR101801 (AACR2018)	N/A	非霍奇金淋巴瘤	-	BR101801	醖襯繭鑰膚遞艱夢構選(餘獵鹹鹽蓋齋簾襯餘鹽) = 糧鏇遞餘選鏇蓋選蓋鬱選餘衊範鹽範繭構窪醖 (糧願製顧簾繭夢鬱網壓 )	-	2018-07-01