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近年来，靶向蛋白降解是新药研发的热点领域，可以用于靶向此前不可成药的靶点，通过降解与疾病相关的蛋白治疗多种疾病，解决传统小分子或生物大分子无法解决的难题。小分子靶向蛋白降解药物（TPDs）诸如蛋白降解靶向嵌合体（PROTACs）、CRBN E3连接酶调节剂（CELMoDs）、分子胶等，被设计用于靶向疾病相关的细胞内蛋白，通过将其传输到泛素-蛋白酶体系统进行降解。这些靶向蛋白降解药物具有许多优点，包括其催化机制、细胞内渗透性和靶向多种蛋白的潜力。有许多全球公司正在开发的蛋白降解药物处于临床前阶段，有望在1-2年内提交新药临床试验（IND）申请，将药物推进早期临床试验阶段。其中包括Arvinas、Kymera和C4 Therapeutics等。Arvinas计划在2023年结束之前为四款临床前药物递交IND申请。C4 Therapeutics计划在今年4月的AACR会议上展示3种蛋白降解药物的临床前数据，预计到2022年底至少将其中2种药物推入临床试验阶段。根据公开信息不完全统计，截至2022年3月25日，全球共有临床前阶段蛋白降解药物108个（不包括中国公司，下同），其中至少有6家公司开发的18个靶向蛋白降解药物在2022年或2023年会有重要的里程碑。下面将对这6家公司的18个临床前蛋白降解药物进行详细介绍。
Arvinas目前拥有多个处于临床前开发阶段的蛋白降解药物。公司预计到2023年底，将会提交4个候选药物的IND申请。公布公开信息的11款临床前药物中8个与实体瘤和血液癌症有关。另外3个药物主要针对神经退行性疾病。对于神经退行性疾病，Arvinas设计的蛋白降解药物具有易于口服给药、穿过血脑屏障和进入中枢神经系统的特性。该公司已经证明其针对帕金森病的蛋白降解药物——α突触核蛋白靶向PROTAC可以在小鼠模型中产生效果。候选药物“mHTT靶向PROTAC”旨在通过选择性地靶向和降解突变的亨廷顿蛋白来治疗亨廷顿舞蹈病。候选药物“tau靶向PROTAC”主要针对阿尔茨海默病。A2A Pharmaceuticals专注于开发肿瘤、耐药性细菌感染和其他危及生命的疾病的新型药物。该公司的SCULPT技术是一种基于片段的重新设计，能够将人工智能结合到药物发现过程中的技术。SCULPT技术结合基于蛋白质-配体相互作用预测以及深度学习算法，用于结构-活性关系分析和新化学实体的创建。A2A的候选药物A2A-O-03正在进行临床前的早期开发，针对KRAS突变的癌症，公司计划在2023年上半年提交IND申请。C4 Therapeutics的TORPEDO平台结合了强大的化学引擎、专有的测试技术、高通量筛选和预测模型，可高效地发现和设计高质量的候选药物，专注于新型蛋白降解疗法药物的开发。C4 Therapeutics将在2022年4月的美国癌症研究协会（AACR）会议上展示三种蛋白降解药物的临床前数据。该公司预计到今年年底，至少将其中两种药物推进临床试验，并完成第三种药物支持IND的研究。CFT-8634靶向BRD9，目前正在开发针对滑膜肉瘤和实体瘤的治疗。今年3月，CFT-8634被美国FDA授予治疗滑膜肉瘤的孤儿药资格。该药物的IND申请在2月底获得许可，预计在今年上半年开始针对滑膜肉瘤患者的1期临床试验。CFT-1946是BRAF V600X突变体的选择性蛋白降解药物，预计将于2022年下半年提交IND申请，并开始1期试验。CFT-8919是一种高效、高选择性的口服EGFR L858R蛋白降解药物，2021年的临床前试验表明，这种蛋白降解药物具有克服耐药突变的潜力，预计将在2022年底完成支持IND的研究。Kymera Therapeutics开发的靶向MDM2的蛋白降解药物KT-253在临床前实验中，已经表现出优于MDM2小分子抑制剂的活性，能够稳定p53的水平，并且导致癌细胞的死亡。通常MDM2小分子抑制剂的使用会导致细胞通过反馈通路，生成更多的MDM2蛋白，导致小分子抑制剂失效。而KT-253由于靶向降解MDM2蛋白，可以克服这一反馈通路的影响。在动物模型中，单剂KT-253治疗可以导致持久的肿瘤消退，这一蛋白降解药物具有治疗多种血液癌症和实体瘤的潜力。Kymera Therapeutics计划在2022年中递交KT-253的IND申请。Monte Rosa Therapeutics的药物发现平台，将专有的小分子蛋白降解药物化合物库与内部的蛋白质组学、结构生物学、基于机器学习的靶点筛选技术和计算化学相结合，用于预测和获得蛋白质降解剂图谱。Monte Rosa Therapeutics开发的蛋白降解药物，旨在改善细胞渗透性、生物利用度和中枢神经系统穿透力。MRT-2359是一种分子胶，靶向GSPT1，用于治疗肺癌、B细胞淋巴瘤、乳腺癌和卵巢癌等多种癌症。Monte Rosa Therapeutics预计在2022年中提交主导项目蛋白降解药物MRT-2359的IND申请。Prelude Therapeutics专注于发现和开发靶向关键癌细胞通路的小分子疗法，用于治疗具有未满足临床需求的癌症。Prelude Therapeutics正在开发一系列针对SMARCA2的蛋白降解药物。开发靶向SMARCA2/4亚基降解剂的研究证明在降解SMARCA2/4的同时，SWI/SNF复合体的其它亚基也同时得到清除。这一结果强调了选择最容易被降解的亚基进行靶向，从而导致整个复合体降解这一开发策略的可行性。当前PreludeTherapeutics正在研究多种高选择性和有效性的SMARCA2降解项目，包括PRT-SCA2，并计划在2022年下半年递交IND申请，预计针对非鳞状非小细胞肺癌（NSCLC）的1期临床试验将于2023年开始。
Drug developers continue to seek new ways to attack difficult protein targets and expand the druggable proteome. The challenge is to find new modalities that engage these difficult targets where traditional small molecules or larger biomolecules have failed. A flexible approach to targeted protein degradation that engages a multiplicity of disease-causing protein targets and eliminates them from within or outside of a cell could be broadly applicable means of addressing traditionally undruggable targets.Modalities such as proteolysis targeting chimeras (PROTACs), cereblon E3 ligase modulators (CELMoDs), molecular glues and a host of similar approaches are being designed to target and eliminate disease-associated intracellular proteins by shuttling them to the ubiquitin-proteasome system for degradation. These small molecule, targeted protein degraders (TPDs) have a number of advantages including their catalytic mechanism, intracellular permeability and potential to target a wide variety of proteins. There is a large cohort of companies developing TPDs in discovery and preclinical stages. Many will be filing investigational new drug (IND) applications and entering early stage clinical trials in 2022 and 2023. These include the major players such as Arvinas, Kymera and C4 Therapeutics with multiple new TPDs in early development. Arvinas reports a preclinical pipeline of 11 drugs and they intend to carry at least 4 to IND by 2023. C4 Therapeutics will be presenting preclinical data on three new drugs at the American Association of Cancer Research meeting in April of this year and the company expects to bring at least 2 of these into the clinic by the end of 2022. In addition to milestones from these and other clinical-stage developers, we expect to see many new drugs and developers reach the clinic by the end of this year.According to incomplete statistics of public information (collected by 3/25/2022), there were 108 preclinical stage protein degradation drugs in the world (besides China), among which at least 18 targeted protein degraders (TPDs) will be filing investigational new drug (IND) applications and entering early stage clinical trials in 2022 and 2023, being developed by 6 different companies. We profiled 6 companies that could make major R&D advances.
（By WuXi AppTec content team. Click the image to view at full size）Arvinas has a lot of PROTACs in preclinical development. These have reached the point of preclinical development where the company anticipates filing at least 4 INDs through 2023. Arvinas has three candidates aimed at targets involved in neurodegenerative disorders. For neurodegenerative diseases, Arvinas is designing PROTACs with properties suitable for transport across the blood-brain barrier, entry into the cells of the CNS and oral dosing. The company has shown that its tau protein and alpha-synuclein PROTACs can degrade disease causing aggregates in mouse models. A preclinical candidate in its neuroscience portfolio is aimed at treating Huntington’s disease by selectively targeting and degrading mutant huntingtin protein. The candidate drug "tau-targeted PROTAC" is mainly targeted at Alzheimer's disease.A2A Pharmaceuticals currently has a small molecule protein degrader in its preclinical pipeline, targeting KRAS for the treatment of solid tumors. A2A uses its proprietary SCULPT platform to discovery small molecules that can engage difficult protein targets for a variety of indications including cancer, infection and autoimmune disease. SCULPT combines compound libraries, computational systems and artificial intelligence to iteratively design, filter and optimize new small molecules that can engage difficult to reach binding domains within protein targets. A2A-O-03 is approaching early preclinical development and the company aims to file an IND in first half of 2023. The drug targets all KRAS mutations and will enable treatment of a broad population of patients.
C4 Therapeutics leverages its proprietary "TORPEDO" platform (Target Oriented Protein Degrader Optimizer) for discovering new targeted protein degraders. TORPEDO integrates comprehensive data on a large body of high quality degraders with E3 ligase structural biology and computational tools to support a chemistry platform that enables design of new degraders and optimization of their potency and specificity. C4 uses TORPEDO to discover both MonoDAC (molecular glues) and BiDAC, heterobifunctional degraders. C4 Therapeutics will be presenting preclinical data on three new drugs at the American Association of Cancer Research meeting in April of 2022. The company expects to bring at least 2 of these into the clinic by the end of the year and complete IND-enabling studies for the third.
CFT-8634 targets BRD9 and is being developed for the treatment of synovial sarcoma and SMARCB1-null solid tumors. CFT-8634 was granted orphan designation for the treatment of soft tissue sarcoma in March. The drug cleared the IND hurdle in late February and the company expects to begin phase 1 trials for synovial sarcoma before the end of the first half of the year. CFT-1946 is a selective degrader of mutant BRAF V600X. The company is developing the drug for the treatment of V600 mutant solid tumors. An IND will be submitted and phase 1 trial started in the second half of 2022. CFT-8919 is a potent and highly selective, orally bioavailable degrader of EGFR L858R. C4 hopes to develop this drug for treating patients who have developed resistance to first-line EGFR inhibitors. Preclinical in vitro and in vivo work reported in 2021 showed that this degrader had broad coverage of on-target resistant mutations and intracranial activity. C4 expects to complete IND enabling studies by the end of 2022.Kymera Therapeutics is developing KT-253, a small molecule degrader of MDM2 E3 ligase for the treatment of solid tumors. MDM2 lies in the p53 tumor suppression pathway and small molecule inhibition is an approach being the taken by a number of developers currently in the clinic. However, incomplete inhibition of MDM2 induces a feedback loop that limits its impact on the p53 pathway. Complete degradation of MDM2 knocks out the feedback loop, leading to upregulation of MDM2 p53 tumor suppression. Therefore, degradation by KT-253 could be superior to current small molecule inhibitors. The general mechanism of action of KT-253 makes it a great candidate for the treatment of a wide variety of cancers. KT253 is currently in IND enabling studies and Kymera projects it will file for an IND in the second half of 2022. Monte Rosa Therapeutics is designing molecular glue degraders intended to have improved cellular permeability, oral bioavailability and CNS penetration. The company is applying a proprietary discovery platform called "Quantitative and Engineered Elimination of Neosubstrates" which combines AI for degron discovery, a growing library of rationally designed degrons and a "Gluomics toolbox" of in vitro and in silico tools to discover and advance their candidate molecular glue degraders. MRT-2359 targets GSPT1, a regulator of MYC-induced translational addiction in tumors. MRT-2359 is being developed to treat a variety of cancers including lung cancer, B-cell lymphomas and breast and ovarian cancers. Monte Rosa expects to submit an IND for its lead program, MRT-2359 in mid-2022.Prelude Therapeutics is a clinical-stage precision oncology company focused on discovery and development of small molecule therapeutics that target the key drivers of cancer cell growth, resistance and survival. Prelude is in the process of progressing a number of protein degraders targeting SMARCA2. Studies on the development of inhibitors targeting the SMARCA 2/4 subunit demonstrated that other subunits of the SWI/SNF complex were simultaneously eliminated by the degradation of SMARCA 2/4. The current Prelude program has identified multiple, highly selective and potent degraders SMARCA2 including PRT-SCA2 and intends to complete IND-enabling studies and make an application for an IND in the second half of 2022. Phase 1 studies in NSCLC are expected to start in 2023.参考来源：
[1] Pioneering the future of targeted protein degradationtherapeutics. Retrieved March 25, 2022 from, https://ir.arvinas.com/static-files/ae957f0c-ac1a-42c7-883a-4aca15c06762
[2] C4Therapeutics Reports Full Year 2021 Financial Results and Recent BusinessHighlights. Retrieved March 25, 2022from, https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-reports-full-year-2021-financial-results-and
[3] From Serendipity to Rational Design Taking MolecularGlue Degraders to New Heights. Retrieved March 25, 2022 from,https://ir.monterosatx.com/mwginternal/de5fs23hu73ds/progress?id=x1JZpwjX59bg0DJN0OU-tXPV104kxCWiAJUYL43BSts,&dl
[4] C4 Therapeutics Announces FDA Orphan Drug Designationfor CFT8634 for the Treatment of Soft Tissue Sarcoma. Retrieved March 25, 2022from, https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-announces-fda-orphan-drug-designation-cft8634
[5] C4 Therapeutics Announces 2022 Key Milestones toAdvance Targeted Protein Degradation Portfolio. Retrieved March 25, 2022 from, https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-announces-2022-key-milestones-advance-targeted
[6]C4Therapeutics Presents Pre-clinical Data on CFT8919, A Selective Degrader ofEGFR L858R, at Keystone Symposium on Targeted Protein Degradation. RetrievedMarch 25, 2022 from,https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-presents-pre-clinical-data-cft8919-selective
[7] UNITED STATES SECURITIES AND EXCHANGE COMMISSION.Retrieved March 25, 2022 from,https://investors.kymeratx.com/static-files/8f97bb5f-311b-479d-b34c-fae12aa4c151
[8]Builda fully integrated oncology company on the foundation of drug discoveryexcellence to deliver
novel precision cancer medicines to underserved patients.Retrieved March 25, 2022 from,https://investors.preludetx.com/static-files/339f87e8-8eb5-4932-b666-5eefeed0a7a2
[9] PIPELINE overview of A2A Pharmaceuticals. RetrievedMarch 25, 2022 from, https://www.a2apharma.com/copy-of-oncology-1
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