Recludix Pharma, Inc.

SAN DIEGO, Nov. 25, 2024 (GLOBE NEWSWIRE) -- Recludix Pharma, a leader in discovery of inhibitors of challenging targets for inflammatory disease, today announced that members of Recludix’s management will participate in two investor conferences in December. Citi 2024 Global Healthcare Conference in Miami, FL Meetings on Tuesday, December 3, 2024 Evercore HealthCONx Conference in Miami, FL Fireside chat on Wednesday, December 4, 2024 from 3:25 – 3:45 p.m. ETLive and archived webcast available: https://recludixpharma.com/events-presentations/ About RecludixRecludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders of Seagen, Blueprint Medicines, and Lilly. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases, as well as additional programs. Recludix was named a 2024 Fierce 15 biotech company. For more information, please visit the company’s website at https://recludixpharma.com. Recludix ContactsMatt Caldemeyer Chief Business Officermcaldemeyer@recludix.com Alexandra Santos asantos@wheelhouselsa.com Aljanae Reynoldsareynolds@wheelhouselsa.com

前言 Kymera Therapeutics一直以来都是我最为欣赏的PROTAC公司，这一点之前的文章已经提过很多次。STAT6 PROTAC KT-621这个项目是其最为看重的项目之一，其出色的临床前数据也为PROTAC在自免领域的发展再次添上了浓墨重彩的一笔【PROTAC希望之光：Kymera口服STAT6  PROTAC KT-621临床前数据公开】。 KT-621已于今年10.24进入一期临床，预计2025年上半年公布一期初步结果。 毋庸置疑，KT-621是一个万众瞩目的项目。然而直至今日，Kymera的STAT6 PROTAC项目尚仅有一篇缺乏实施例，只能称作是平台技术的专利WO2024064080A1（保护了已报道所有STAT6抑制剂与E3连接酶配体的组合），公开于2024.3.28。这对于fastfollower企业来说，属实有点无从下手。 这篇专利并非没有提供有价值的信息。本来想等等看化合物专利的，现在属实是等不了了。下面就根据这篇345页的专利，抽丝剥茧，窥探一下KT-621的大致结构。 既然PROTAC作为一个三元复合的双功能化合物。便从E3 ligand、Linker、warhead三个部分来进行结构分析。不过本专利并未对Linker做任何详细描述，仅重点表述了warhead与E3 ligand。因此仅分析这两个部分。 本文是对前瞻篇内容【STAT6 PROTAC:从专利中推测KT-621的大致结构（前瞻篇）】的后续介绍。 E3 ligand 这个部分其实比较简单。首先看一下Kymera的临床项目KT-474、KT-253结构，以及其专利中挖掘的TYK2/CDK2 PROTAC专利中代表性结构。 可见这些均无一例外的采用了同样的CRBN配体，也许这一结构便是Kymera充分验证的高选择性且成药性最佳的优势CRBN配体。鉴于KT-621也是一款口服制剂，其CRBN配体很有可能也是采用这一结构。 专利中的信息也能间接证明这一点： 至于Kymera为何在诸多CRBN配体中唯独偏爱这一构型，也值得分析一二。众所周知，自免类药物对化合物的安全性有高要求，这也需要化合物具有极高的选择性。 鉴于CRBN广泛的底物以及沙利度胺类IMiDs杂乱的靶点，基于这类配体的PROTAC也可能对这类靶点一定的降解活性（下图b）。因此选择一个仅与CRBN高亲和活性而对其他靶点无降解活性的“干净”配体则是非常关键点。一篇JMC文献（J. Med. Chem. 2022, 65, 747−756）也许证明了这一点，Cpd.10（下图）对IKZF1/3、CK1α等靶点均无降解活性,证明其高选择性。 现在很多公司的PROTAC改造都在CRBN配体上做文章，导致现在CRBN配体纷繁多样（下图，列举部分），Kymera也对这些骨架进行了保护。 Kymera还在专利中保护了诸多E3相关ligand，如VHL、IAP、MDM2、DCAF15、KEAP1、DCAF1等等。当然考虑到成药性等问题，选择这些E3的可能性不高。 Warhead 从Kymera目前研究中看，其青睐于通过对成熟抑制剂优化设计PROTAC的策略，因此很难有证据表明Kymera自行开发新型选择性靶向STAT6的抑制剂再进行PROTAC研究。因此warhead很大概率出自上一篇文章分析的目前已公开的一系列STAT6抑制剂【STAT6 PROTAC:从专利中推测KT-621的大致结构（前瞻篇）】：将28个骨架分成了三类：1.普通芳杂环类，低参考价值；2.MNC的高活性STAT6抑制剂；3.磷酸肽类抑制剂。那么，28个骨架结构，到底哪个会是KT-621的warhead呢？ 第一类应该可以先排除点，这类化合物结构简单，活性较差，应该难以作为PROTAC的warhead。 那么Kymera是否会从MNC的高活性STAT6抑制剂中寻找warhead？ 由于这些专利年份过早，缺乏结构生物学证据或是生物学实验数据表明这类化合物是直接靶向STAT6，且具有高选择性。基于上述某个抑制剂warhead的PROTAC能否实现高活性与高选择性，犹未可知。但相信这个可能性偏低。 那么，是否有可能是磷酸肽类抑制剂呢？ 首先我们捋一下KT-621的研发时间线： 2024.01.04 Kymera首次公开STAT6 PROTAC KT-621，确认PCC 2024.03.08 Kymera首次公开KT-621的临床前数据 2024.10.24 KT-621的一期临床研究开始，并于2024.11.05公示 按照药明的说法（多半也是Kymera的CMC合作方），对于小分子候选化合物，从PCC到IND的时间可缩短至9至12个月。同样，new modalities的测试和制造时间表可以压缩为 12 至 18 个月。 KT-621作为new modality，按最快12个月计算，实际PCC确认时间大致在2023年10月，考虑Lead to PCC的时间，Kymera确认Lead的时间大致在2023年7月之前。 从专利WO2024064080A1的优先权日可以看到，Kymera早在2022年便已开始STAT6 PROTAC项目，优先权更新在2022-10-25后沉寂了9个月。2023-07-21/2023-09-12这两个优先权，均是在Recludix的磷酸肽类STAT6抑制剂公开不久后更新。从这两个优先权文件中也能证明，Kymera在优先权文本中补充了与WO2023133336A1/WO2023164680A1相关的马库什式，作为一种防御性的保护。因此磷酸肽类warhead这种思路似乎并不在Kymera的早期研发规划中。与此同时，由于Recludix的STAT3/6 PROTAC专利WO2024233639A2近期公开，Kymera的专利WO2024064080A1的马库什专利优先权能否成立就得掂量掂量了。 不过磷酸肽类抑制剂并非是Recludix首创，正如【靶向STAT6：磷酸肽类抑制剂，漫漫长路】中所描述的，德克萨斯大学John S. McMurray团队在磷酸肽类STAT6抑制剂的开发作出了巨大的贡献，相信Recludix的研究也是受此启发。WO2014182928A2，PM-71A或其类似物，很可能便是Kymera的warhead参考对象。 或者是PM-81I为代表的磷酸肽前药的形式（下图，或者是出自J. Med. Chem. 2015, 58, 8970−8984）。 这一点就和王少萌的AK-1690有点相似了，但AK-1690无法口服是最大的弊病。 当然也不排除Kymera会根据STAT3抑制剂/PROTAC母核优化的经验，设计与KT-333类似的母核结构，但可能性偏低。 不过还有一点，这类化合物最大的问题是如何优化磷酸肽类抑制剂/PROTAC的成药性。Recludix已经实现了口服STAT3抑制剂磷酸肽前药的成药性优化，似乎也实现了STAT3 PROTAC的成药性优化【Recludix研发进展与STAT3/6 PROTAC专利分析】，但STAT6的相关优化似乎仍存在问题。Kymera如果真是基于此的优化，成药性的突破是最值得期待的一点。 后话 总而言之，Kymera的KT-621很可能是基于德克萨斯大学John S. McMurray团队所开发的磷酸肽类STAT6抑制剂。但以上均是个人猜测，目前的数据还是无法揭开KT-621的庐山真面目，只能等待后续公开了。 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓

-REX-7117 is an oral, potent and selective STAT3 SH2 domain inhibitor, which demonstrated strong efficacy in an in vivo model of inflammatory arthritis -STAT3 inhibition does not impair the interferon-mediated antiviral defense or hematopoietic growth factor signaling, as seen with JAK/TYK2 inhibitors SAN DIEGO, Nov. 14, 2024 (GLOBE NEWSWIRE) -- Recludix Pharma, a leader in discovery of inhibitors of challenging targets for inflammatory disease, today announced pre-clinical inflammatory arthritis data for REX-7117, an oral, reversible, SH2 domain-targeting STAT3 inhibitor, will be presented at the American College of Rheumatology (ACR) Convergence meeting being held November 14–19, 2024 in Washington, D.C. In multiple in vivo models of inflammatory arthritis, REX-7117 achieved deep, durable, and selective STAT3 inhibition, decreased inflammatory biomarkers such as c-reactive protein (CRP), and achieved statistically significant efficacy compared to vehicle and comparable efficacy to a high-dose of the JAK inhibitor, baricitinib. Unlike both JAK1/2 and pan-JAK inhibitors, REX-7117 did not impair innate interferon-dependent viral replication or growth factor signaling critical for hematologic homeostasis. “We have multiple preclinical datasets in inflammatory diseases confirming the differentiated therapeutic potential of selectively targeting STAT3,” said Ajay Nirula, M.D., Ph.D., executive vice president and head of research and development. “In these most recent studies for arthritis, we have demonstrated that by inhibiting STAT3, we can potently dampen inflammatory cytokines that drive rheumatologic diseases. Importantly, we are able to do so while avoiding the pathways that trigger the safety concerns seen with JAK/TYK2 inhibitors. A selective STAT3 inhibitor could be a promising therapy for diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease.” REX-7177 was found to: Be highly selective to STAT3, including across the SH2 domain family and other STAT proteins;Achieve deep and durable STAT3 inhibition;Dose-dependently reduce arthritis disease clinical scores, similar to the highest dose of baricitinib tested;Significantly reduce serum CRP, an IL-6 dependent biomarker of inflammatory activity;Effectively reduce histopathological changes, including inflammation, cartilage damage, pannus formation, periosteal proliferation and bone resorption;And, not impair either type I or type II interferon-mediated antiviral activity. In contrast, the JAK inhibitors tofacitinib and baricitinib broadly inhibited multiple phosphoSTAT pathways. JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated hematologic homeostasis (anemia, thrombocytopenia). Poster Presentation Details: Title:REX-7117 Is a Highly Potent and Selective Oral STAT3 Inhibitor That Demonstrated Potential Efficacy and Safety Differentiation versus JAK/TYK2 Targeting in Preclinical Models of Inflammatory ArthritisPoster Number:0947Session:Poster Session B, RA – Animal Models PosterDate and Time:Sunday, November 17, 2024; 10:30 a.m. - 12:30 p.m. ET About STAT3The interleukin cytokines IL-23 and IL-6 signal through STAT3 and promote the generation and function of pathogenic T helper type-17 (Th17) cells, a type of immune cell that is pro-inflammatory. Th17 cells are considered pivotal players in certain inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others. Inhibiting STAT3 can also offer potential efficacy beyond Th17 / IL-17 driven diseases in clinical indications where blocking the IL-6 pathway is clinically validated. Furthermore, clinical trials inhibiting oncostatin M (OSM) and IL-22, both STAT3 dependent cytokines, have been reported as efficacious in inflammatory disease. A selective, oral STAT3 inhibitor has potential to provide an attractive alternative to JAK/TYK2 inhibitors and biologics for multiple inflammatory diseases. About RecludixRecludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders of Seagen, Blueprint Medicines, and Lilly. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases, as well as additional programs. Recludix was named a 2024 Fierce 15 biotech company. For more information, please visit the company’s website at https://recludixpharma.com. Recludix ContactsMatt Caldemeyer Chief Business Officermcaldemeyer@recludix.com Alexandra Santos asantos@wheelhouselsa.com Aljanae Reynoldsareynolds@wheelhouselsa.com