公开(公告)号：US20170001958A1

公开(公告)日：2017-01-05

申请号：US15103619

申请日：2014-12-12

Applicant: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Inventor： David T. CHUANG ,  Shih-Chia TSO ,  Xiangbing QI ,  Wen-Jun GUI ,  Cheng-Yang WU ,  Jacinta L. CHUANG ,  Uttam K. TAMBAR ,  R. Max WYNN

IPC: C07D209/44 ,  C07D401/12

CPC classification number: C07D209/44 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D487/08

Abstract: The present disclosure relates to the identification of PDK inhibitors and their use in the treatment of diseases such as diabetes, cardiovascular disease and cancer. The invention relates to the development of robust PDK inhibitors that can be used to improve glucose metabolism and correct metabolic dysfunction in vivo. Based on the unique structural features present in the ATP-binding pocket of PDK2, a single functional-group change was made in a known Hsp90 inhibitor that binds to the corresponding pocket of the latter protein from the GHKL family. This approach efficiently converted the Hsp90 inhibitor to a highly specific inhibitor for all PDK isoforms. These final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues.

Abstract translation: 本公开涉及PDK抑制剂的鉴定及其在治疗糖尿病，心血管疾病和癌症等疾病中的用途。 本发明涉及可用于改善体内葡萄糖代谢和纠正代谢功能障碍的强力PDK抑制剂的开发。 基于PDK2的ATP结合口袋中存在的独特的结构特征，在已知的Hsp90抑制剂中进行单个官能团变化，其结合来自GHKL家族的后一种蛋白质的相应口袋。 该方法有效地将Hsp90抑制剂转化为所有PDK异构体的高度特异性抑制剂。 这些系列的这些最终的PDK抑制剂强力地增加PDC活性，减少组织中的磷酸化。

公开(公告)号：US20160250216A1

公开(公告)日：2016-09-01

申请号：US14442485

申请日：2013-11-14

Applicant: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Inventor： Richard K. BRUICK ,  Charles G. CALDWELL ,  Doug E. FRANTZ ,  Kevin H. GARDNER ,  John B. MACMILLAN ,  Thomas H. SCHEUERMANN ,  Uttam K. TAMBAR

IPC: A61K31/519 ,  A61K31/4184 ,  A61K31/4192 ,  A61K31/4245 ,  A61K31/136

CPC classification number: A61K31/519 ,  A61K31/136 ,  A61K31/4184 ,  A61K31/4192 ,  A61K31/4245

Abstract: Provided is a method of inhibiting heterodimerization of HIF-2α to HIF1β (ARNT) comprising binding certain small molecules to the HIF-2α PAS-B domain cavity but not to HIF1α and inhibiting HIF-2α heterodimerization to HIF1β (ARNT) but not inhibiting HIF1α heterodimerization to HIF1β (ARNT). Those certain small molecules are also referenced synonymously as HIF2-HDI and HIF2α heterodimerization inhibitors and also simply as certain small molecules.

Abstract translation: 提供了抑制HIF-2α对HIF1β（ARNT）的异二聚化的方法，其包括将某些小分子与HIF-2αPAS-B结构域腔结合而不是HIF1α，并抑制HIF-2α异二聚化为HIF1β（ARNT），但不抑制HIF1α 异源二聚化为HIF1β（ARNT）。 这些特定的小分子也被称为HIF2-HDI和HIF2α异二聚体抑制剂，也简称为某些小分子。