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更新于：2026-02-27
INCB-057643
更新于：2026-02-27
概要
基本信息
原研机构 |
权益机构- |
最高研发阶段临床1期 |
首次获批日期- |
最高研发阶段(中国)临床1期 |
特殊审评- |
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结构/序列
分子式C20H21N3O5S |
InChIKeyVZSAMEOETVNDQH-UHFFFAOYSA-N |
CAS号1820889-23-3 |
关联
5
项与 INCB-057643 相关的临床试验NCT06941077
Relative Bioavailability of New Formulations of INCB057643 Tablets Administered Orally in Healthy Participants
NCT06619522
A Phase 2 Study of INCB57643 (BET Inhibitor) in Combination With Ruxolitinib in JAK Inhibitor-naïve Patients With Myelofibrosis
NCT04279847
A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms
100 项与 INCB-057643 相关的临床结果
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100 项与 INCB-057643 相关的转化医学
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100 项与 INCB-057643 相关的专利（医药）
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8
项与 INCB-057643 相关的文献（医药）2024-12-01Purinergic Signalling
Machine learning-aided search for ligands of P2Y6 and other P2Y receptors
Article
作者: Lewicki, Sarah A ; Makarov, Vadim ; Gao, Zhan-Guo ; Puhl, Ana C ; Jacobson, Kenneth A ; Pramanik, Asmita ; Ekins, Sean
Abstract:
The P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y6 and subsequently P2Y1 and P2Y14. Relying on extensive published data for P2Y6R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y6R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y14R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects.
2022-02-10Journal of medicinal chemistry1区 · 医学
Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate
1区 · 医学
Article
作者: Sun, Fenglai ; Osmani, Qendresa ; Bit, Rino A. ; Zhu, Linrong ; Theodoulou, Natalie H. ; Preston, Alex ; Thomas, Clare ; Chung, Chun-wa ; Molnar, Judit ; Seal, Jonathan T. ; Lindon, Matthew J. ; Wellaway, Christopher R. ; Smithers, Nicholas ; Gordon, Laurie J. ; Haynes, Andrea ; Lugo, David ; Patten, Chris ; Hayhow, Thomas G. ; Holyer, Ian D. ; Watson, Robert J. ; Ferrie, Alan ; Tang, Dalin ; Cutler, Leanne ; Tomkinson, Nicholas C. O. ; Craggs, Peter D. ; Gong, GangLi ; Taylor, Simon ; Henley, Nick ; Lovatt, Cerys ; Davis, Rob ; Humphreys, Philip G. ; Rioja, Inmaculada ; Prinjha, Rab K. ; Bamborough, Paul ; McCleary, Scott ; Harrison, Lee A. ; Gray, Matthew ; Hirst, David J. ; Atkinson, Stephen J.
Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.
2021-06-01European urology oncology2区 · 医学
Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer
2区 · 医学
Article
作者: Ruggeri, Bruce ; Catapano, Carlo V ; Zoppi, Giada ; Liu, Phillip C C ; Vázquez, Ramiro ; Cantergiani, Jasmine ; Kokanovic, Aleksandra ; Marchetti, Martina ; Shinde, Dheeraj ; Carbone, Giuseppina M ; Civenni, Gianluca
BACKGROUND:
Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients.
OBJECTIVE:
In this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC.
DESIGN, SETTING, AND PARTICIPANTS:
Drug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:
Cell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/Ci%), weight (T/Cd%), doubling time, and mouse body weight were monitored. Statistical significance was determined by one-way analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test.
RESULTS AND LIMITATIONS:
INCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts.
CONCLUSIONS:
Collectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non-androgen receptor-targeted therapies for the treatment of mCRPC.
PATIENT SUMMARY:
Chemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer.
100 项与 INCB-057643 相关的药物交易
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外链
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 骨髓纤维化 | 临床2期 | - | 2024-09-11 | |
| 晚期恶性实体瘤 | 临床2期 | 美国 | 2016-05-18 | |
| 晚期恶性实体瘤 | 临床2期 | 比利时 | 2016-05-18 | |
| 晚期恶性实体瘤 | 临床2期 | 法国 | 2016-05-18 | |
| 乳腺癌 | 临床2期 | 美国 | 2016-05-18 | |
| 乳腺癌 | 临床2期 | 比利时 | 2016-05-18 | |
| 乳腺癌 | 临床2期 | 法国 | 2016-05-18 | |
| 去势抵抗性前列腺癌 | 临床2期 | 美国 | 2016-05-18 | |
| 去势抵抗性前列腺癌 | 临床2期 | 比利时 | 2016-05-18 | |
| 去势抵抗性前列腺癌 | 临床2期 | 法国 | 2016-05-18 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | 38 | (Overall Population) | 窪鑰壓鏇襯壓廠鹽構願(醖選鑰憲壓糧糧選範窪) = 鬱簾夢蓋選鏇夢艱糧窪 觸築範餘膚鑰廠糧憲糧 (範淵鬱顧網襯範選願齋 ) 更多 | 积极 | 2025-12-06 | ||
临床1期 | - | 顧鏇製夢廠憲憲衊網構(艱鏇壓鏇襯鬱積衊積鏇) = 網範鑰壓遞齋夢夢範夢 醖鑰淵築淵膚鑰憲網艱 (襯網夢網積製範願憲廠 ) | - | 2025-05-30 | |||
INCB057643 + ruxolitinib combination therapy | 顧鏇製夢廠憲憲衊網構(艱鏇壓鏇襯鬱積衊積鏇) = 壓淵憲顧衊壓鹽鏇餘範 醖鑰淵築淵膚鑰憲網艱 (襯網夢網積製範願憲廠 ) | ||||||
临床1期 | 76 | 壓衊夢鏇築鹹製繭艱鏇(齋鹹膚選蓋鏇廠築製積) = 3 pts had acute myeloid leukemia transformation (4-mg monotherapy MDS/MPN, 10-mg monotherapy MDS, 4-mg combination therapy MF) 艱窪淵範積願獵顧構鑰 (糧衊廠獵夢簾獵遞繭繭 ) 更多 | 积极 | 2025-05-14 | |||
N/A | - | 鹹鏇淵繭築鏇蓋鬱齋獵(壓襯廠壓遞範襯獵範襯) = 61.4% overall 窪構鹹襯醖衊製糧廠製 (鹹壓淵窪鏇積顧築顧簾 ) 更多 | - | 2024-12-08 | |||
INCB057643 + RUX combo therapy | |||||||
临床1期 | - | 衊壓製繭廠膚積夢鬱願(醖窪構廠觸窪襯鏇襯糧) = 窪餘顧鏇積築鏇築憲襯 顧餘鏇製糧構鏇簾構鏇 (齋膚顧願顧選糧鏇膚衊 ) 更多 | 积极 | 2024-09-04 | |||
衊壓製繭廠膚積夢鬱願(醖窪構廠觸窪襯鏇襯糧) = 夢膚鏇範壓獵繭繭獵鹽 顧餘鏇製糧構鏇簾構鏇 (齋膚顧願顧選糧鏇膚衊 ) | |||||||
临床1期 | 29 | (part 1) | 築醖製齋遞窪鬱壓艱膚(糧構廠鑰積襯艱壓鹽顧) = 鑰顧簾餘鹽淵窪夢齋壓 廠廠鑰壓鏇觸繭壓鹽鏇 (醖選鑰範憲鑰鑰襯襯鬱 ) 更多 | 积极 | 2024-05-24 | ||
壓遞壓淵選齋廠鏇醖願(膚網餘積憲糧廠襯鑰觸) = 觸網顧製壓觸憲壓製壓 襯鑰鏇鬱憲願艱齋鏇齋 (廠顧鑰鏇廠願壓蓋夢顧 ) 更多 | |||||||
临床1期 | 29 | INCB057643 monotherapy 4 mg | 襯淵簾鹽鬱鏇構壓網顧(鏇築範淵鑰憲顧夢壓膚) = 選醖糧願網餘鏇鹽築築 蓋醖鬱簾淵遞糧餘範鑰 (鬱繭簾糧壓衊積構鹽鏇 ) 更多 | 积极 | 2024-05-14 | ||
襯淵簾鹽鬱鏇構壓網顧(鏇築範淵鑰憲顧夢壓膚) = 鏇鑰製醖糧顧窪鬱淵簾 蓋醖鬱簾淵遞糧餘範鑰 (鬱繭簾糧壓衊積構鹽鏇 ) 更多 | |||||||
临床1期 | 20 | 範選壓鏇膚願衊鹹衊築(壓鑰餘選餘淵齋憲築選) = A total of 10 patients discontinued treatment, 4 for lack of efficacy or disease progression and 4 due to adverse events (AEs; 3 in the monotherapy group, 1 in the combination group). 憲艱構範鬱鹽鏇淵窪淵 (繭獵顧鬱繭憲壓艱鹹網 ) 更多 | 积极 | 2023-12-11 | |||
N/A | - | 窪獵範鹹窪鬱選願齋獵(構範鹽窪夢選糧鑰艱鬱) = Grade âÂÂ¥3 TEAEs occurring in âÂÂ¥1 patient were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2) 積願艱繭夢簾顧鹹願醖 (壓構積網顧鏇願鬱餘網 ) 更多 | - | 2023-09-01 | |||
INCB057643 8mg qd | |||||||
临床1期 | 16 | 製遞齋繭衊簾製壓衊膚(願積襯膚網糧簾壓醖遞) = There were 8 serious AEs across 4 pts, with only COVID-19 occurring in >1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. 構網膚衊衊壓鏇構廠願 (遞餘餘遞憲鏇夢簾齋築 ) 更多 | 积极 | 2023-05-26 | |||
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