作者: Wang, Mi ; Sun, Duxin ; Jiang, Wei ; Wang, Yu ; Xu, Renqi ; Zhao, Lijie ; Meagher, Jennifer L ; Kirchhoff, Paul D ; Wang, Shaomeng ; Wang, Meilin ; McEachern, Donna ; Metwally, Hoda ; Jiang, Hui ; Wen, Bo ; Bai, Longchuan ; Kaneshige, Atsunori ; Stuckey, Jeanne A

Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

2023-02-23·Journal of medicinal chemistry1区 · 医学

Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia

1区 · 医学

Article

作者: Wang, Mi ; Meagher, Jennifer L. ; McEachern, Donna ; Stuckey, Jeanne A. ; Wang, Shaomeng ; Xu, Renqi ; Sun, Duxin ; Bai, Longchuan ; Wen, Bo ; Kirchhoff, Paul D. ; Kaneshige, Atsunori

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules.

项与 AK-2292 相关的新闻（医药）

2023-03-06

·生物谷

Nat Chem Biol：科学家有望利用一种新方法直击“无成药性”靶点帮助开发新型癌症疗法

来自密歇根大学等机构的科学家们通过研究发现了一种新方法或能“击中”这一“无成药性”靶点。长期以来，蛋白质STAT5一直被认为是一种非常诱人的抵御癌症的靶点，但经过科学家们几十年的研究后发现，其或许会被归类到“无成药性”（undruggable）的类别，近日，一篇发表在国际杂志Nature Chemical Biology上题为“A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo”的研究报告中，来自密歇根大学等机构的科学家们通过研究发现了一种新方法或能“击中”这一“无成药性”靶点。通过利用细胞垃圾处理功能，研究人员发现他们或能从细胞培养物和小鼠机体中消除STAT5，并未癌症疗法的开发奠定潜在的基础。STAT5在机体某些血液癌症的发生和进展过程中扮演着关键角色，但科学家们在识别一种能阻断STAT5功能的小分子抑制剂方面一直备受阻碍。此前研究结果表明，设计一种能以高度亲和力结合STAT5的药物或许具有一定的挑战性，而这是一种衡量其结合程度的方法，即使当一种化合物被发现能结合该蛋白，其或许也无法进入到细胞和组织中，而找到一种仅能抑制STAT5而不影响其它任何STAT 蛋白功能的化合物似乎非常困难。研究者Shaomeng Wang的实验室一直在研究能靶向作用蛋白质降解的新型药物开发手段，蛋白质降解是细胞内部移除不想要的蛋白质的一种天然发生功能，我们可以将其想象成为一种垃圾处理系统，当蛋白质不再需要维持机体健康时，这种机制就会从细胞中移除不需要或损伤的蛋白质。利用这一方法，研究者Wang的实验室就识别出了一种能靶向作用并移除STAT5的蛋白质降解子—AK-2292，该化合物对STAT5蛋白具有高度亲核性，而对其它的STAT蛋白却没有任何影响效应，其能被细胞系和小鼠模型有效摄入，且被发现能在人类慢性随性白血病（CML）中阻断细胞系的生长，并能在CML小鼠模型中诱导肿瘤的消退。科学家有望利用一种新方法直击“无成药性”靶点帮助开发新型癌症疗法。图片来源：Nature Chemical Biology (2023). DOI: 10.1038/s41589-022-01248-4 蛋白质的降解能通过从肿瘤细胞和组织中消除STAT5蛋白质来发挥作用，其并不像传统的小分子抑制剂那样被设计地能与蛋白质结合并干扰其功能。研究者Wang说道，我们已经克服了一些阻碍科学家们靶向作用STAT5的主要问题，过去20年里有些研究人员一直从事这项领域的研究，目前还没有能靶向作用STAT5的小分子进入到临床开发中。而本文研究结果表明，如今研究人员能通过蛋白质降解的手段来靶向作用STAT5，这或许是一种新型令人兴奋的研究方向，研究人员可以开发用于癌症疗法的靶向作用STAT5的潜在药物分子，而其中该蛋白扮演着重要的角色。这种化合物为后期科学家们进一步研究优化并识别出最终能推动临床开发的新型化合物奠定了坚持的基础；多年来，研究者Wang的实验室一直在调查蛋白质降解子，如今其已经在先进的临床前开发研究中拥有了一些降解子，他们希望这或许会推动后期科学家们开发癌症疗法的相关临床试验。综上，本文研究结果表明，AK-2292不仅能作为一种强大的工具，而且还能用于研究STAT5的生物学特性，以及展现出选择性STAT5蛋白质剔除和抑制的治疗潜力，但同时其也是一种非常有潜力的先导化合物，最终或有望帮助开发STAT5靶向性疗法。（生物谷Bioon.com）原始出处： Atsunori Kaneshige,Longchuan Bai,Mi Wang, et al. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo, Nature Chemical Biology (2023). DOI: 10.1038/s41589-022-01248-4

蛋白降解靶向嵌合体

2023-02-20

·World Pharma News

Researchers use a new approach to hit an 'undruggable' target

The protein STAT5 has long been an appealing target against cancer, but after decades of research it was consigned to the "undruggable" category. Now, University of Michigan Rogel Cancer Center researchers have found success with a new approach. By tapping into a cellular garbage disposal function, researchers found they could eliminate STAT5 from cell cultures and mice, setting the stage for potential development as a cancer treatment. STAT5 plays a key role in how some blood cancers develop and progress. But efforts to identify a small molecule inhibitor to block STAT5 have been stymied. Previous research efforts have found it challenging to design a drug to bind to STAT5 with a high-affinity, a measure of how well they fit together. Even when a compound was found to bind with the protein, it may not make its way into cell and tissue. It's also difficult to find a compound that inhibits STAT5 only without affecting any of the other STAT proteins. Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor in Medicine and professor of medicine, pharmacology and medicinal chemistry at the University of Michigan, had another idea. His lab has been working on a new drug development approach targeting protein degradation. This is a naturally occurring function within cells to get rid of unwanted protein. Think of it as the garbage disposal: When a protein is no longer needed to keep a body healthy, this mechanism removes the unwanted or damaged protein from the cell. Using this approach, Wangs lab identified a protein degrader, AK-2292, that targets and removes STAT5. The compound was highly specific to STAT5 with no effect on other STAT proteins. It was effectively taken up by both cell lines and mouse models and was found to stop cell growth in cell lines of human chronic myeloid leukemia (CML) and to induce tumor regression in mouse models of CML. Results are published in Nature Chemical Biology. The protein degrader works by eliminating STAT5 proteins from tumor cells and tissues, unlike a small molecule inhibitor that would traditionally be designed to bind with the protein and interfere with its function. "We've overcome some of the major issues that were barriers for scientists to target STAT5," Wang said. "People have worked in this field for the last 20 years, and there are no small molecules targeting STAT5 going into clinical development. This study shows us STAT5 can be targeted through a protein degradation approach. It's a new, exciting direction for developing a potential drug molecule targeting STAT5 for the treatment of cancers in which this protein plays a major role. "This compound gives us a very solid foundation to do further optimization to identify a compound that we eventually can advance into clinical development," Wang added. Wang's lab has been investigating protein degraders for several years and has a number of degraders in advanced preclinical development studies, which they hope will lead to clinical trials for the treatment of cancer in people. Kaneshige A, Bai L, Wang M, McEachern D, Meagher JL, Xu R, Wang Y, Jiang W, Metwally H, Kirchhoff PD, Zhao L, Jiang H, Wang M, Wen B, Sun D, Stuckey JA, Wang S. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nat Chem Biol. 2023 Feb 2. doi: 10.1038/s41589-022-01248-4

蛋白降解靶向嵌合体

100 项与 AK-2292 相关的药物交易

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