LFM-A13: An antileukemic/antithrombotic agent

LFM-A13：抗白血病/抗血栓药物

• 批准号: 6840009
• 负责人: TARACAD VENKATACHALAM
• 金额: $ 37.81万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6840009
• 关键词: anticoagulants; antineoplastics; antithrombins; chemosensitizing agent; collagen; dogs; drug design /synthesis /production; laboratory rat; leukemia; neoplasm /cancer chemotherapy; oral administration; pharmacokinetics; platelet activation

DESCRIPTION (provided by applicant): We have rationally designed the leflunomide metabolite analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) as a specific inhibitor of the protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 is a chemosensitizing anti-leukemic agent with anti-thrombotic properties. Our preclinical studies established that LFM-A13 has a favorable safety and pharmacokinetics profile. LFM-A13 has been formulated for oral administration (LFM-A13-F). Under SPECIFIC AIM 1, we will study the toxicity profile of LFM-A13-F in rats and dogs and 2) synthesize and formulate large quantities of LFM-A13 under GMP conditions to be used for human clinical trials. Based on the toxicity studies done in mice, we hypothesize that LFM-A13-F will not cause acute, subacute, or chronic toxicity at the proposed dose levels. Under SPECIFIC AIM 2, large scale synthesis and evaluation of LFM-A13-F as hard gelatin capsules will be carried under Good Manufacturing Practice (GMP) to comply with FDA regulations and to ensure preparation of clinical grade LFM-A13-F for human clinical trials. We will use synthetic procedures developed during the phase I studies. In order to achieve specific aim 2 we have already identified FDA approved facilities for the synthesis and formulation of LFM-A13. The results obtained in specific aim #1 and specific aim #2 will provide the critical information for further testing of this agent in human subjects under Phase III. This research will facilitate the bench-to-bedside development of LFM-A13 as the protype of a new class of anti-leukemic agents with anti-thrombotic properties.

描述（由申请人提供）：我们合理设计了来氟米特代谢物类似物α-氰基-β-羟基-β-甲基-N-（2，5-二溴苯基）-丙烯酰胺（LFM-A13），作为蛋白酪氨酸激酶布鲁顿酪氨酸激酶（BTK）的特异性抑制剂。LFM-A13是一种具有抗血栓形成特性的化学增敏性抗白血病药物。我们的临床前研究证实LFM-A13具有良好的安全性和药代动力学特征。LFM-A13已配制用于口服给药（LFM-A13-F）。在特定目标1下，我们将研究LFM-A13-F在大鼠和犬中的毒性特征，2）在GMP条件下合成和配制大量LFM-A13用于人体临床试验。基于在小鼠中进行的毒性研究，我们假设LFM-A13-F在拟定剂量水平下不会引起急性、亚急性或慢性毒性。在特定目标2下，将根据良好生产规范（GMP）进行LFM-A13-F硬明胶胶囊的大规模合成和评价，以符合FDA法规并确保制备用于人体临床试验的临床级LFM-A13-F。我们将使用I期研究期间开发的合成程序。为了实现具体目标2，我们已经确定了FDA批准的用于合成和配制LFM-A13的设施。具体目标#1和具体目标#2中获得的结果将为III期研究中该药物在人类受试者中的进一步试验提供关键信息。这项研究将促进LFM-A13作为一类具有抗血栓性质的新型抗白血病药物的原型的实验室到床边的发展。

项目成果

Large-scale synthesis of GMP grade alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a new anti-cancer drug candidate.

大规模合成GMP级α-氰基-β-羟基-β-甲基-N-(2,5-二溴苯基)丙烯酰胺(LFM-A13)，一种新的抗癌候选药物。

• DOI: 10.1055/s-0031-1296599
• 发表时间: 2007
• 期刊: Arzneimittel-Forschung
• 作者: DuMez,Darin;Venkatachalam,TaracadK;Uckun,FatihM
• 通讯作者: Uckun,FatihM

Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13).

布鲁顿酪氨酸激酶靶向抗白血病候选药物 α-氰基-β-羟基-β-甲基-N-(2,5-二溴苯基)丙烯酰胺 (LFM-A13) 的临床前毒性和药代动力学。

• DOI: 10.1055/s-0031-1296583
• 发表时间: 2007
• 期刊: Arzneimittel-Forschung
• 作者: Uckun,FatihM;Tibbles,Heather;Venkatachalam,Taracad;DuMez,Darin;Erbeck,Douglas
• 通讯作者: Erbeck,Douglas