近日，标新生物和上海科技大学范高峰团队在国际知名期刊《Cell Chemical Biology》在线发表了题为“NAMPT-targeting
PROTAC and nicotinic acid co-administration elicit safe and robust
anti-tumor efficacy in NAPRT-deficient pan-cancers”的封面文章，报道了新一代靶向NAMPT蛋白的PROTAC降解剂同时阻断NAMPT蛋白的酶活和非酶活功能，当与烟酸联用时，在NAPRT缺陷的泛癌中展现出优异的安全性和强效的抗肿瘤作用。
图1
NAD+（烟酰胺腺嘌呤二核苷酸）是氧化还原反应的辅酶，参与能量合成和DNA修复等多种生理过程。NAD+在机体内共有三条合成途径，NAMPT作为合成NAD+补救途径的关键限速酶在多种肿瘤细胞中高表达，这使其成为癌症治疗的潜在靶点。NAMPT一方面在细胞内以iNAMPT的形式发挥酶活功能，负责NAD+的生物合成；另一方面还能分泌到细胞外以eNAMPT的形式发挥非酶活功能，促进肿瘤发生发展。前期靶向NAMPT的策略主要集中在传统酶活抑制剂的开发，但在临床上效果不佳。标新生物和上海科技大学科研团队在先前的研究中利用PROTAC技术开发了两种化合物SIAIS630120和SIAIS630121，能够同时降解iNAMPT和eNAMPT两种形式的NAMPT蛋白，但是出现了与传统抑制剂类似的毒性问题。因此，解决靶向NAMPT带来的毒副作用至关重要。
研究团队首先验证了多种肿瘤细胞对靶向NAMPT的PROTAC化合物的敏感性，发现靶向NAMPT的PROTAC化合物在NAPRT缺陷的肿瘤细胞中具有更好的杀伤效果，因此提出将NAPRT缺陷的癌症作为靶向NAMPT蛋白的PROTAC化合物的适应症，同时联用烟酸（Nicotinic Acid）给药以减弱NAMPT靶点的毒副作用。
图2 NAPRT缺陷的肿瘤细胞对靶向NAMPT的PROTAC化合物敏感
鉴于先前开发的两种靶向NAMPT的PROTAC化合物在100 nM的浓度下出现了明显的“Hook effect”，所以研究团队在先前PROTAC化合物的基础上优化得到了新一代的靶向NAMPT的PROTAC化合物（632005），632005具有低IC50和高降解效率，同时代谢稳定性更优异。
图3 第二代靶向NAMPT的PROTAC化合物设计及构效关系分析
在得到632005化合物之后，研究团队进一步验证了靶向NAMPT的PROTAC化合物联用烟酸减弱毒性作用的可行性。如图4所示，632005处理之后会显示出一定的毒性作用，包括血常规各项指标异常，而回补烟酸之后可以有效地减弱632005导致的毒性作用，因此，靶向NAMPT的PROTAC化合物632005与烟酸联用是一项可行的减弱NAMPT靶点毒性作用的策略。
图4 回补烟酸可逆转靶向NAMPT的PROTAC化合物的毒性
为了进一步评估联用烟酸给药对PROTAC抗肿瘤作用的影响，研究团队构建了血液恶性肿瘤、前列腺癌的异种移植模型以及来源于病人的肝癌PDX模型，如图5所示，证明了靶向NAMPT的PROTAC化合物联用烟酸在NAPRT缺陷的泛癌中具有显著的抗肿瘤效果。
图5 NAMPT-PROTAC联用烟酸在NAPRT缺陷的泛癌中具有强大的抗肿瘤药效
总的来说，研究团队发现靶向NAMPT的PROTAC化合物在NAPRT缺陷的肿瘤细胞中具有更好的杀伤效果。之后开发了第二代的PROTAC化合物632005，当与烟酸联合使用时，能有效地减弱毒副作用，并且在NAPRT缺陷的泛癌中显示出强大的抗肿瘤药效。
标新生物作为通讯单位与学术机构合作再发文章，进一步展示了GlueTacs®平台上丰富的技术储备和转化潜力，也体现出该平台重要的学术价值和商业潜力。
《Cell Chemical Biology》文章链接：https://www.cell.com/cell-chemical-biology/abstract/S2451-9456(24)00208-3Recently, Gluetacs Therapeutics and Fan
Gaofeng lab from ShanghaiTech University have published an online cover article
titled "NAMPT-targeting PROTAC and nicotinic acid co-administration elicit
safe and robust anti-tumor efficacy in NAPRT-deficient pan-cancers" in the
internationally renowned journal Cell Chemical Biology. The article
reports that a new generation of PROTAC degrader targeting the NAMPT protein
simultaneously blocks the enzymatic and non-enzymatic functions of the NAMPT
protein, and when combined with nicotinic acid, it has shown safety and robust
anti-tumor efficacy in NAPRT-deficient pan-cancers.NAD+(Nicotinamide Adenine Dinucleotide) is a coenzyme involved in redox reactions
and various physiological processes such as energy synthesis and DNA repair.
There are three synthetic pathways for NAD+ in the body, and NAMPT,
as a key rate-limiting enzyme in the NAD+ salvage pathway, is highly
expressed in various tumor cells, making it a potential target for cancer
treatment. On the one hand, NAMPT functions enzymatically in cells in the form
of iNAMPT, responsible for the biosynthesis of NAD+; on the other hand,
it can also be secreted outside the cell in the form of eNAMPT to exert
non-enzymatic functions, promoting tumor development. Previous strategies
targeting NAMPT have mainly focused on the development of traditional enzymatic
inhibitors, but their clinical results were poor. In a previous study, the
research team developed two compounds, SIAIS630120 and SIAIS630121, using
PROTAC technology, which can degrade both iNAMPT and eNAMPT. However, toxicity
issues similar to traditional inhibitors have emerged. Therefore, addressing
the side effects of targeting NAMPT is crucial.The
research team first validated the sensitivity of various tumor cells to PROTAC
targeting NAMPT and found that PROTAC targeting NAMPT had a better efficacy in
NAPRT-deficient tumor cells. Therefore, the research team proposed NAPRT-deficient
cancers as the potential indications for PROTAC targeting NAMPT protein and
combined nicotinic acid to mitigate the side effects.Given
that the two previously developed PROTAC targeting NAMPT have exhibited a
significant "Hook effect" at a concentration of 100 nM, the research
team optimized the previous PROTAC to obtain a new generation of PROTAC targeting
NAMPT (632005). 632005 has low IC50, high degradation profile and
excellent metabolic stability.After
obtaining the compound 632005, the research team further validated the
feasibility of combining PROTAC targeting NAMPT with nicotinic acid to mitigate
toxicity. 632005 treatment exhibited certain side effects, including
abnormalities in various blood routine indicators, while nicotinic acid
supplementation can effectively mitigate the side effects caused by 632005.
Therefore, combining PROTAC 632005 targeting NAMPT with nicotinic acid is a
feasible strategy to mitigate the side effects of NAMPT targeting.To
further evaluate the impact of combining nicotinic acid administration on the
anti-tumor efficacy of PROTAC, the research team constructed xenograft models
of hematologic malignancies, prostate cancer, and patient-derived liver cancer
PDX models, and demonstrated that PROTAC targeting NAMPT
combined with nicotinic acid can exhibit significant anti-tumor efficacy in
NAPRT-deficient pan-cancers.In
summary, the research team found that PROTAC targeting NAMPT has a better efficacy
profile in NAPRT-deficient tumor cells, and then developed a second-generation
PROTAC, 632005. When combined with nicotinic acid, it effectively
mitigated side effects and showed robust anti-tumor efficacy in NAPRT-deficient
pan-cancers.Gluetacs Therapeutics, by publishing this article with academic institutions as a corresponding affiliation, has once again demonstrated the rich technical reserve and translational potential of the GlueTacs® platform, as well as its significant academic valuation and commercial potential.
标新生物（Gluetacs Therapeutics）是一家专注于研发口服蛋白降解小分子药物的生物医药公司，为上海科技大学孵化的首家生物医药公司，成立于2020年2月，2021年3月正式运营，由多名在蛋白降解领域深耕多年的科学家领衔创立。公司拥有自主知识产权的分子胶降解剂（GLUE）和双机制降解剂（GLUETAC）开发平台，并拥有申请和授权不同国家该领域专利近百项，具备独具特色的差异化技术路线和发展战略。公司现已自主建立人工智能虚拟筛选平台、体外药效筛选平台、药代动力学平台、蛋白质组学平台以及肿瘤动物药效模型平台，实现了完备的全流程药物研发体系建设。标新生物自从2021年3月正式运营以来，成功推动两个候选药物进入临床试验，充分验证和体现了GlueTacs®平台快速发现候选药物和管线推进的能力。标新生物自成立以来受到业内的广泛关注，连续三年获得上海市科技型中小企业称号，荣获2024专精特新中小企业和创新型中小企业称号、2024年度临港新片区科创新锐企业称号、2023上海市高价值专利运营大赛百强、2023中国海归创业大赛三等奖、2023华医榜中国生物医药科技创新价值榜最具成长性小分子创新药企业TOP10、2023临港杯第九届创青春上海青年创新创业大赛一等奖、2022浦东新区全球高校校友科创大赛二等奖，2022中国创新制药企业TOP10、2022第十一届中国创新创业大赛成长组全国赛优秀企业奖、2022第6届医疗健康投资卓悦榜年度生物医药最佳企业、2022第五届中国创翼创业创新大赛上海选拔赛浦东赛区十佳创翼奖、2022浦东新区全球高校校友科创大赛二等奖、2022Venture50新芽榜150强、2021年度全国颠覆性技术创新大赛优秀项目、2021年第二届生物产业年度攀登榜年度最具投资潜质的新锐BioTech、2021中国生物医药产业链创新风云榜金马奖最具关注度新锐企业TOP10奖项。公司陆续获得多项科技部和上海市科委资金支持，纳入临港新片区前沿产业优秀人才安家补贴、重点产业人才补贴、人才引进重点机构名单，知识产权管理体系获得中国专利保护协会认证，多位团队核心成员陆续获得临港新片区十大科技创新先锋人物、谈家桢生命科学产业化奖、杨雄科技创业奖、东方英才创业青年领军人才、上海高层次海外人才和上海市浦江人才等称号。公司也先后成为上海科技大学创新型硕士和工程博士培养单位，并先后与十多位海内外专家教授进行科研研究合作。
About Gluetacs TherapeuticsGluetacs Therapeutics, focusing on the development of oral small molecule protein degrader, is the first biotech company incubated from ShanghaiTech University, Gluetacs was founded in February 2020, and started to operation in March 2021. It was founded by several scientists that have done intensive studies in target protein degradation. The company has independent intellectual property of GLUE degrader and GLUETAC degrader development platform with around 100 patents filed, which has indicated a unique and differentiated technical route and development strategy. The company has established artificial intelligence virtual screening platform, in vitro pharmacodynamics screening platform, pharmacokinetics platform, proteomics platform and in vivo drug pharmacology evaluation platform, and has constructed a complete whole-process drug R&D system. Since its operation in March 2021, Gluetacs Therapeutics has successfully advanced 2 drug candidates into phase I clinical trial, which has demonstrated the GlueTacs® platform's ability to rapidly discover drug candidates and promote pipelines.
