protac 简介（桑迪亚搭建PROTAC研发平台）
protac 简介（桑迪亚搭建PROTAC研发平台）PROTAC药物作用机制示意图。PROTAC与目标靶蛋白（POI）和E3连接酶结合形成三元复合物，随后将泛素以E2介导的方式转移到POI上。蛋白酶体识别多泛素化的POI，并在PROTAC释放以参与另一个循环过程时降解。PROTAC的结构看起来像一个哑铃，通过一个连接器（linker）连接目标蛋白的配体以及E3泛素连接酶（E3 ubiquitin ligase）的招募配体。也就是说，PROTAC小分子连接体的一端与靶向蛋白结合，另一端与E3泛素连接酶结合。E3泛素连接酶通过将一种叫做泛素（ubiquitin）的小分子蛋白贴在靶向蛋白上，将其标记为缺陷或受损蛋白，就好像是给“垃圾”打上了可回收的标记，之后，细胞的蛋白粉碎机（即蛋白酶体 Proteases）会处理掉被标记的靶蛋白。单抗虽然相对于小分子具有高亲和力和高选择性的优势，但其最大弊端在于无法透过细胞膜，因此无法作用于细胞内靶点。RNA
传统的小分子药物研发大部分是通过以下步骤完成的。首先找到影响疾病进展的蛋白质靶点，并通过高通量筛选找到针对这个靶点的苗头化合物。然后再通过很多轮的分子设计、合成、测试找到一个高活性的可以调节这个靶蛋白活性的化合物，同时进行PK/PD的优化以及动物毒性检测等，最终确定一个候选化合物分子。再通过临床I、II、III期试验，获得监管部门批准而成为一个药物。
2020年新冠疫情席卷全球，让人们更加重视生命健康，也给生物医药行业带来了机遇。以PROTAC技术为代表的等诸多前沿领域技术持续获得关注重点。过去十年，药物靶标领域的格局发生了重大变化。尽管传统靶标生物药（如激酶，G蛋白偶联受体等）依然如火如荼，但是研发重点已慢慢从传统药物靶标转向更具挑战性的“不可成药”靶标。这些靶标通常包括无酶功能的蛋白质，而这些蛋白占据人体蛋白的80%左右。随着靶向诱导蛋白降解技术(Proteolysis targeting chimeras PROTAC)的发展，其在克服耐药和靶向不可成药靶点方面展现出了非常大的潜力。
研发背景
传统的小分子抑制剂的作用机制是通过结合靶蛋白的活性位点从而抑制靶蛋白的功能，100多年来小分子的研发思路成功对抗了很多疾病。但小分子成药的技术也面临着诸多的限制和挑战，例如小分子药物会出现耐药性，无法长期抑制靶向蛋白的活性；且小分子药物需要维持一定的体内药物浓度才能发挥作用；另外，还有很多靶点被认为是小分子所无法靶向的，如一些转录因子，骨架蛋白和无药可治的突变靶点KRAS等。
单抗虽然相对于小分子具有高亲和力和高选择性的优势，但其最大弊端在于无法透过细胞膜，因此无法作用于细胞内靶点。RNAi可以透过细胞膜，并对靶点有强作用力，然而由于其代谢不稳定及脱靶效应等弊端，发展进程也是困难重重。
PROTAC技术的出现给小分子药物的瓶颈带来了曙光，可以完美地解决小分子药物面临的诸多难题。2001年，PROTAC首次作为化学生物学方法和新的治疗方法被提出来，经过20年的发展，PROTAC技术已日趋成熟。很多突破性的研究显著加速了该领域的发展，学术界和工业界的许多科研小组致力于探索PROTAC蛋白质降解技术的应用。
作用机理
PROTAC的结构看起来像一个哑铃，通过一个连接器（linker）连接目标蛋白的配体以及E3泛素连接酶（E3 ubiquitin ligase）的招募配体。也就是说，PROTAC小分子连接体的一端与靶向蛋白结合，另一端与E3泛素连接酶结合。E3泛素连接酶通过将一种叫做泛素（ubiquitin）的小分子蛋白贴在靶向蛋白上，将其标记为缺陷或受损蛋白，就好像是给“垃圾”打上了可回收的标记，之后，细胞的蛋白粉碎机（即蛋白酶体 Proteases）会处理掉被标记的靶蛋白。
PROTAC药物作用机制示意图。PROTAC与目标靶蛋白（POI）和E3连接酶结合形成三元复合物，随后将泛素以E2介导的方式转移到POI上。蛋白酶体识别多泛素化的POI，并在PROTAC释放以参与另一个循环过程时降解。
PROTAC技术的独特之处
常规的小分子和抗体药物只能靶向人体中约10-20％的蛋白质，有超过80%的肿瘤靶点目前仍无法用传统的抑制剂解决，由于PROTAC药物所具有的催化特性，调动的是人体自身的天然蛋白降解系统UPS，因此可以针对“不可成药”或“难以成药”的靶点进行药物开发。另外，目前的肿瘤靶向药耐药问题比较严重，主要由于靶蛋白突变导致传统抑制剂的结合力降低，而PROTAC技术无需高结合力即可高效降解靶蛋白。
PROTAC技术在克服耐药性和靶向不可成药靶点方面展现出了非常大的潜力。作为PROTAC技术的代表公司Arvinas，目前处于临床I-III期的两个PROTAC药物ARV-110（靶向雄激素受体，治疗前列腺癌）和ARV-471（靶向雌激素受体，治疗乳腺癌），都展现出了积极的治疗数据。
PROTAC与小分子抑制剂和基因药物的对比，资料来源：Arvinas
PROTAC技术的优缺点
PROTAC的优点是不仅可以有效地抑制目标蛋白，还可以快速降解清除。只需要催化量的药物，就可以降解细胞内靶标蛋白，故具有较高的安全性、耐药性和广阔的应用前景。
尽管PROTACs已表现出显著的有效性，但是仍有许多不足的地方需要解决。
1. PROTACs分子量一般在700~1200之间，这使得它们的透膜能力与(口服)生物利用度较差，且缺少如适用于小分子药物的“类药五原则”的预测模型，这使得目前大部分的研究仅仅证明了所设计的PROTAC在细胞水平上对靶蛋白降解的有效性与抗增殖活性。
2. 与传统小分子药物不同，目前尚无有效的高通量筛选技术用于快速、大量地评估PROTAC降解POI的能力，只能通过细胞活性筛选或免疫印迹实验等方法实现，这大大降低了开发PROTAC的速度与成功率。
3. 有文献报道，仅仅改变linker的长度或结构就会对PROTAC的降解能力有巨大影响，这或许是由于在泛素化过程中不同的E3酶和POI之间所需的空间距离不同引起的。鉴于目前仍没有POI-Protac-E3酶复合物的晶体结构被解析得到，因此对linker部分的改造缺少指导方向。
4. 发现与E3酶受体蛋白特异性结合的底物具有偶然性，目前报道的PROTAC主要靶向CRBN与VHL，尽管CRBN与VHL是否会发生突变以及突变后是否对PROTAC有影响还是未知，但了解新的E3酶并开发相应的PROTAC具有重要意义，也面临巨大挑战。
PROTAC与目标靶蛋白和E3连接酶结合形成三元复合物，蛋白酶体识别并降解多泛素化的靶蛋白，PROTAC被释放以参与另一个循环降解过程，这一复杂的作用过程，使得PROTAC的药物研发相较于传统小分子药物难度大大增加。
搭建PROTAC研发平台——保诺—桑迪亚的优势
保诺-桑迪亚是一家领先的生命科学研发公司，专业为生物制药客户和合作伙伴提供从靶标识别到IND申报及用于临床试验的药品GMP生产的一体化药物研发服务。作为世界第三大CRDMO公司（合同研究、工艺开发和生产公司），保诺-桑迪亚在全球10大分支机构拥有超过2 000名团队成员，在中国和美国开展其主要业务。公司设药物化学、药代动力学、药研生物学、药效学、肿瘤等专业研发部门和运营团队，拥有国际一流技术与设施，拥有在各领域世界一流的药物研发人员和科学家队伍。
肿瘤学是保诺—桑迪亚一直重点发展的疾病领域。公司的肿瘤学部门致力于提供高品质的临床前服务，提供2D或3D细胞模型和动物肿瘤模型以支持抗癌药物的发现。拥有经验丰富的科研小组和多个已验证的细胞模型和癌症动物模型的研发服务平台，公司协助制药企业和学术研究机构开发新的药物靶点，并给抗癌化合物或生物药进行临床前的全面评估。
保诺—桑迪亚的药研生物学、药代动力学已到达国际领先水平，为几百家国内外的新药研发机构和公司提供了高质量的研发服务。保诺—桑迪亚凭借强大的研发能力，建立了特异性强、灵敏度高和重现性好的蛋白类药物的定量分析方法，搭建起生物小分子靶向诱导蛋白降解技术PROTAC研发平台。
2021年1月，考虑到PROTAC技术有可能是颠覆小分子药物研发的一种非常有潜力的新技术，结合公司多年来在靶向药物研发方面积累的丰富经验，保诺—桑迪亚正式启动设立了基于PROTAC技术的研发平台。
“自PROTAC技术问世以来，我们一直在跟进这一技术的发展，我们在该领域积累了丰富的基因编辑技术和靶向开发经验，这对于我们搭建PROTAC研发平台是一个天然的优势。为了尽快将这一先进技术融入保诺—桑迪亚的研发中，我们正式启动了PROTAC研发平台项目。” 保诺—桑迪亚李翔博士说。
保诺—桑迪亚的PROTAC研发专项研究小组，由资深分子生物学博士作为项目负责人，项目组成员具有深厚的癌症及分子生物学科研背景、具有长期从事分子药物表征和药代的多种生物分析平台的工作经验，同时，成熟的小分子PK分析平台和动物实验室为搭建PROTAC研发分析平台提供了保障。
“保诺—桑迪亚的PROTAC研发平台主要是基于Promega公司的HiBiT小标签和细胞内NanoBRET 技术，利用前沿的CRISPR基因编辑技术和高通量筛选技术，同时优化整合现有的各种细胞生化实验技能，用阳性化合物和阴性化合物来进行终点检测和实时动态检测，分析数据，汇合参数。同时优化其它现有内源性蛋白表达相关检测技术，利用各种技术的优劣势，完成靶标蛋白质降解的多样化检测。“，保诺—桑迪亚李翔博士介绍道：”保诺—桑迪亚的PROTAC研发平台能为大量客户提供了高品质的小分子靶向研发服务。使靶点从“无成药性”变成“有成药性”，帮助客户研发出更多更有效的靶向可成药。“
HiBiT小标签示意图
细胞内NanoBRET技术
展望未来，李翔博士预测，一方面，靶向可成药靶点的PROTAC分子可能会获批上市；另一方面，一些靶向不可成药靶点的PROTAC分子会被开发出来，展现出PROTAC技术真正的优势，从而为一些目前难以治疗的疾病探索新的革命性疗法。保诺—桑迪亚在未来几年，会搭建起技术成熟的PROTAC研发平台，帮助越来越多的客户扩展小分子靶向药的适应证研发，同时针对一些不可成药的靶点开发PROTAC分子。
李翔博士表示：“作为一种开创性技术，PROTAC的潜力是无限的，尤其在靶向不可成药靶点方面的应用非常令人期待。前些年，制药界的大部分热情都投放在了大分子生物药，而PROTAC技术的出现填补了小分子靶向药研发的一些空白，包括针对难成药靶点、克服小分子抑制剂耐药性等，PROTAC技术重燃了小分子药物公司的研发热潮。随着学术界、产业界以及投资界都加大对这一技术的投入，相信PROTAC会给药物研发带来颠覆性的影响。“
保诺—桑迪亚一站式PROTAC性能检测平台研究技术方案流程图
“保诺—桑迪亚将建立全面综合的PROTAC研发平台，提供灵敏的高通量化合物筛选检测方法，从各个层面分析和比较候选化合物的功效和性能，全力支持靶点设计、优化和改造，将会有效解决PROTAC药物研发的通量低、化合物作用机制复杂等困难，对PROTAC药物的早期研发意义重大。”
靶标-PROTAC-E3连接酶三元复合体的形成、泛素化和蛋白酶体降解示意图
保诺—桑迪亚PROTAC技术研发平台特点：
A．利用CRISPR技术在基因组水平上敲入HiBiT小标签，使用多重方法在基因和蛋白水平上验证内源性靶标蛋白的正确标记，建立可用于高通量筛选的敏感稳定HiBiT细胞株，并用阳性化合物和阴性化合物来进行终点检测和实时动态检测，分析数据，汇合参数。同时优化其它现有内源性蛋白表达相关检测技术，利用各种技术的优劣势，完成靶标蛋白质降解的多样化检测；
B．基于NanoBRET原理，建立相关实验检测PROTAC化合物的透膜性，以及细胞内与蛋白结合效率，结合各种细胞外生化实验，评估PROTAC化合物分别与靶标蛋白和E3连接酶的结合性能。为化合物优化提供数据支持。
C．基于NanoBRET原理，建立相关实验检测细胞内靶标-PROTAC-E3连接酶三元复合体的形成、泛素化和蛋白酶体降解，同时开发特定靶标的TR-FRET生化检测方法，评估PROTAC化合物的性能，为PROTAC研发提供关键数据。
D．在化学部门合成工具化合物，用于验证和优化以上所述的实验平台。
E. 优化并整合现有各种相关检测技术，包括细胞内蛋白表达水平检测，细胞内外蛋白结合，细胞活性等实验，进一步发挥它们在PROTAC研发中的作用。
F. 研究不同的E3连接酶在各种组织和肿瘤中的表达谱，探索发现全新的结合E3连接酶的小分子化合物，为PROTAC的研发提供崭新的工具和方向，以突破现有工具的瓶颈。
总结
保诺—桑迪亚的药研生物部门自成立以来飞速发展，为国内外的新药研发机构和公司提供了高质量的研发服务。随着国内外越来越多的研究机构和药企先后加入PROTAC这一热门领域，众多之前 “不可成药” 的靶点有待开发成PROTAC新型小分子药物。保诺—桑迪亚凭借强大的研发能力，利用自身研发技能，旨在建立一站式PROTAC综合研发平台，为更多的新药研发企业提供全面优质服务。
保诺—桑迪亚将为客户提供PROTAC药物体外全面检测的全流程服务，搭建一站式检测平台，为客户完成PROTAC化合物的各项体外检测评估服务，提供详尽数据以支持候选化合物的进一步化学优化与改造，为众多研发PROTAC药物的机构提供早期研发的综合解决方案。
关于保诺-桑迪亚
保诺-桑迪亚，安宏资本旗下投资企业之一，是业内领先的合同研究、工艺开发和生产公司 (CRDMO)，专业为生物制药客户提供全面整合服务，支持药物发现、开发和生产（包括原料药和成品药）。作为全球第三大 CRDMO 公司，保诺-桑迪亚的 10 大办事处遍布全球，旗下拥有 2000 多名员工，在中国和美国开展主要业务。
保诺-桑迪亚在大小分子发现、开发和放大方面拥有核心专业知识，支持 IND 申报，拥有独特的专利技术平台（例如不溶性化合物生物利用度增强平台）。公司在中国和美国均设有研发中心和生产基地。保诺-桑迪亚采用“一站式”运营模式，有效帮助生物制药客户加快发现进程并降低开发风险，从而创造更高价值的药物。
保诺-桑迪亚由安宏资本领投，Bridgewest Business Group 为共同投资者。
关于安宏资本
安宏资本成立于 1984 年，是全球规模最大且最富经验的私募股权投资基金之一。自成立以来，安宏资本在 41 个国家完成了超过350项私募股权交易。截至 2020 年 6 月 30 日，公司资产管理规模达 584 亿美元。公司在全球四大洲 12 个国家设立了 15 个办公室，并拥有一支超过 200 名专业投资人士的国际团队，业务遍布北美、欧洲、拉丁美洲和亚洲。公司专注于五个核心投资领域 －商业和金融服务业，医疗健康，工业，零售、消费品与休闲，以及科技、媒体和电信业。35 年以来，安宏资本致力于国际投资市场，始终与管理团队保持协作，推动被投公司实现收入和利润的可持续增长。
关于Bridgewest Business Group
Bridgewest Business Group 成立于 1999 年，是一家封闭型投资公司，旨在通过应用卓越的行业经验、专业的运营知识和大量的金融资源，创造长期价值，从而吸引投资机会。集团的全球投资覆盖四个职能领域，包括私募股权、房地产、资本市场和金融服务。私募股权投资主要集中在生物技术、无线通信、物联网基础设施和半导体领域。Bridgewest 总部位于加利福尼亚州圣迭戈，投资业务遍布美国、欧洲、亚洲和大洋洲。
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BioDuro-Sundia has established PROTAC research and development platform
Change “undruggable nature” into “high- druggability”
The development work of the vast majority of these traditional small molecule drugs is done through the following steps. First find the protein target that affects the progression of disease and find the emerging compound aiming at this target by high-throughput screening. Then through many rounds of molecular designing synthesis and detection find a highly-active compound that can regulate the activity of this target protein. At the same time PK/PD optimization and animal toxicity testing are carried out to determine the candidate compound molecule. Finally implement I II and III clinical trials to obtain regulatory approval and become the drug.
The COVID-19 swept across the globe in 2020 which made people pay more attention to their lives and health and also brought huge opportunities to the bio-pharmaceutical industry. Various frontier technologies represented by PROTAC technology continued to gaining much attention. In the past decade great changes have taken place in the landscape of the drug target field. Although those traditional target biological drugs (such as kinases G protein-coupled receptors etc.) are still popular now the focus of research and development has gradually shifted from traditional drug targets to the “undruggable” targets which are more challenging. These targets usually contain enzyme-free proteins that account for about 80% of human proteins. With the development of Proteolysis targeting chimeras (PROTAC) it has shown great potential in overcoming drug resistance and targeting undruggable targets.
R&D background
The mechanism of action of traditional small molecule inhibitors is to inhibit the function of target protein through binding the active site of target protein. For more than 100 years the research and development of small molecule drugs have successfully fought many illness and diseases. However the technology of small molecule drugs also faces many limitations and challenges. For example small-molecule drugs may generate resistance and cannot inhibit the activity of target protein in the long term. And small molecule drugs need to maintain a certain level of internal drug concentration to play its role. Besides there are also many targets that are considered to be untargeted by small molecules such as some transcription factors skeleton proteins and the incurable mutational target KRAS.
Although the monoclonal antibody has the advantages of high affinity and high selectivity compared with small molecules the biggest disadvantage is that it cannot penetrate the cytomembrane and therefore cannot act on intracellular targets. RNAi can penetrate the cytomembrane and has a strong effect on the target. However due to its instability of metabolic and off-target effect the development course of RNAi is also very difficult.
The emergence of PROTAC technology has brought the light to the bottleneck of small molecule drugs which can perfectly solve those problems faced by small molecule drugs. In 2001 PROTAC was first proposed as a chemobiological method and a new treatment method. After 20 years of development PROTAC technology has become increasingly mature. Many breakthrough studies have significantly accelerated the development of this field. And many scientific research groups in academia and industry are dedicated to exploring the application of PROTAC protein degradation technology.
Mechanism of action
The structure of PROTAC looks like a dumbbell. The ligand of the target protein and the recruited ligand of E3 ubiquitin ligase are connected through a linker. In other words one end of the PROTAC small molecule linker is combined with the target protein and the other end is combined with the E3 ubiquitin ligase. The E3 ubiquitin ligase attaches the ubiquitin (a small molecule protein) to the targeted protein and marks it as defective or damaged protein as if placing a recyclable label on "junk". After that the cell's protein grinder (proteases) will process the labeled targeted protein.
Diagram of the mechanism of action of PROTAC drugs
PROTAC combines with POI and E3 ligase to form the ternary complex. Then the ubiquitin is transferred to POI through the E2-mediated method. The proteasome recognizes multi-ubiquitinated POI and releases in PROTAC so as to implement the degradation when participating in another cyclic process.
Unique features of PROTAC technology
The conventional small molecules and antibody drugs can only target about 10%-20% of protein in the human body and more than 80% of tumor targets cannot be solved with traditional inhibitors. Due to the unique catalytic feature of PROTAC drugs the natural protein degradation system UPS in the human body can be mobilized Therefore these “undruggable” or “hard to be druggable” targets can be developed. In addition at present the resistance problem of tumor targeted drugs is especially serious. The leading factor is that the mutation of the target protein reduces the binding force of traditional inhibitors. However the PROTAC technology can efficiently degrade the target protein without high binding force.
The PROTAC technology has shown great potential in overcoming drug resistance and targeting those undruggable targets. As the representative of PROTAC technology Arvinas is carrying out two clinical trial (I-III) about PROTAC drugs and these two trials both show positive treatment data. One is ARV-110 (targeting androgen receptor which is used to treat prostatic cancer) and the other one is ARV-471 (targeting estrogen receptor which is used to treat breast cancer).
Comparison of PROTAC with small molecule inhibitors and gene drugs. Source: Arvinas
Advantages and disadvantages of PROTAC technology
The advantage of PROTAC is not only effectively inhibiting the target protein but also quickly degrading and eliminating the target protein. The catalytic amount of drug can be used to degrade intracellular target protein thus guaranteeing its great safety drug resistance and broad application prospect.
Although PROTACs have shown great effectiveness there are still many shortcomings that need to be solved.
1. The molecular weight of PROTACs is generally between 700 and 1200 which makes their membrane permeability is worse than (oral) bioavailability. At the same time they lack the prediction model such as Rule of Five which is applicable to small molecule drugs. The above-mentioned shortcomings make many of these studies only prove the effectiveness and anti-proliferative activity of the designed PROTAC on the degradation of target protein at the cellular level.
2. Unlike traditional small molecule drugs there is now no effective high-throughput screening technology to rapidly evaluate the degradation ability of PROTAC to POI in abundance. So it can only be achieved through cell activity screening or western blot experiment which greatly reduces the speed and success rate of PROTAC development.
3. According to reports in the literature changing the length or structure of the linker will have a huge impact on the degradation ability of PROTAC which may be caused by the different spatial distances required by different E3 enzyme and POI during the ubiquitination process. Due to the lack of analytic crystal structure of the POI-Protac-E3 enzyme complex the modification of the linker is developing without guidance.
4. It is randomly to find the substrate that combines with the specificity of E3 enzyme receptor protein. At present it is reported that PROTAC mainly targets CRBN and VHL. No one can be sure about the mutation of CRBN and VHL and the corresponding effect on PROTAC in the future. However it is of great significance to understand new E3 enzyme and develop the corresponding PROTAC. At the same time this process is also confronted with great challenges.
In the process firstly PROTAC integrates with the target protein and E3 ligase to form the ternary complex. Then the proteasome recognizes and degrades the multi-ubiquitinated target protein. And PROTAC is released to participate in another cyclic degradation process. This complex process makes the research and development of PROTAC more difficult compared with traditional small molecule drugs.
Build the PROTAC R&D platform - Advantages of BioDuro-Sundia
BioDuro-Sundia is a leading global life sciences research and development company that provides biopharmaceutical clients and partners with comprehensive fully integrated drug research and development services from target identification to IND-enabling studies to GMP manufacture of drug product for clinical trials. As the world’s third largest CRDMO company (contract research process development and manufacturing organization) BioDuro-Sundia has more than 2 000 team members in 10 branches around the world and its main business is carried out in China and the United States. The company not only has professional R&D departments and operation teams in medicinal chemistry DMPK biology pharmacology and oncology but also has global top-class technologies facilities experts and scientists in research and development of drugs from various fields.
Oncology is the key development field for BioDuro-Sundia. The oncology department is committed to providing high-quality pre-clinical services supplying 2D or 3D cell models and animal tumor models to support the research of anti-cancer drugs. With the help of research and development service platform which has the experienced scientific research teams and several verified cell models and cancer animal models the company is able to assist pharmaceutical companies and academic research institutions to develop new drug targets and conduct pre-clinical evaluation on anti-cancer compounds or biological drugs.
The DMPK and Biology of BioDuro-Sundia have reached the leading level in the world providing high-quality R&D services for hundreds of new drug R&D institutions and companies at home and abroad. With its strong R&D capabilities BioDuro-Sundia has established a quantitative analysis method for protein drugs with strong specificity high sensitivity and good reproducibility and has constructed the PROTAC R&D platform for small biological molecules.
In January 2021 considering that PROTAC technology may become a new technology with enormous potential to subvert the research and development of small molecule drugs BioDuro-Sundia officially established the R&D platform based on PROTAC technology with the help of its plentiful experience in the research and development of targeted drugs over the years.
“Since PROTAC technology came into being we have been focusing on the development of this technology. We have accumulated rich experience in gene editing technology and target development in this field which is a natural advantage for us to establish the PROTAC R&D platform. In order to rapidly integrate this advanced technology into the research and development of BioDuro-Sundia we officially launched the PROTAC R&D platform project." Dr. Xiang Li from BioDuro-Sundia said.
The company’s specialized research team for PROTA R&D is in charge of the senior Ph.D. in molecular biology. As for team members they not only have deep research background in cancer and molecular biology but also have long-term working experience in different biological analysis platform for molecular drug representation and pharmacokinetics. At the same time the mature small molecule PK analysis platform and animal laboratory provide solid guarantee for the establishment of the PROTAC R&D analysis platform.
“The PROTAC R&D platform of BioDuro-Sundia is mainly based on the HiBiT small tag of Promega and intracellular NanoBRET technology. On the one hand this platform uses cutting-edge CRISPR gene editing technology and high-throughput screening technology optimizes and integrates various existing cell biochemistry experimental skills uses positive compounds and negative compounds for end-point detection and real-time dynamic detection analyzes data and unites different parameters. On the other hand this platform optimizes other existing detection technologies for endogenous protein expression and uses both advantages and disadvantages of various technologies to complete diversified detection of target protein degradation." Dr. Li Xiang from BioDuro-Sundia said: “The PROTAC R&D platform of BioDuro-Sundia can provide a large number of customers with high-quality small-molecule targeting R&D services change “undruggable” into “druggable” so as to help customers discover and develop more and more effective targeted drugs.
Diagram of HiBiT small tag
Intracellular NanoBRET technology
Of his prospect for the future Dr. Li Xiang predicts that on the one hand PROTAC molecules that targeting druggable targets may be approved for accessing to market; on the other hand some PROTAC molecules that targeting undruggable targets will be developed to show the true advantages of PROTAC technology so as to explore new revolutionary therapies for some existing cureless diseases. BioDuro-Sundia will build a mature PROTAC R&D platform in the next few years to help more and more customers expand the R&D of indications for small molecule targeted drugs and at the same time develop PROTAC molecules for some undruggable targets.
Dr. Li Xiang said: " As a pioneering technology PROTAC has unlimited potential especially in targeting those undruggable targets. In the past few years much attention of pharmaceutical industry has been paid to developing macromolecular biological drugs and the emergence of PROTAC technology has filled gaps in the R&D of small molecule targeted drugs including solving some targets that are hard to be druggable and overcoming resistance of small molecule inhibitors. PROTAC technology has promoted and boosted the R&D of small molecule drug companies. Now not only academic circle but also industrial circle and investment community are increasing their investment in this technology. So I strongly believe that PROTAC will have a disruptive impact on drug development.”
Flow diagram for the research and technical program of BioDuro-Sundia one-stop PROTAC performance detection platform
"BioDuro-Sundia will establish a comprehensive PROTAC R&D platform provide sensitive screening and detection methods for high-throughput compound analyze and compare the function and performance of candidate compounds from all sides and fully support target designing optimization and upgrading. The above measures will effectively solve the R&D difficulties of PROTAC drugs such as low through-put and complex mechanism of action of compound which is of great significance to the early research and development of PROTAC drugs."
Diagram of formation ubiquitination and proteasome degradation of the target-PROTAC-E3 ligase ternary complex
Characteristics of PROTAC R&D platform of BioDuro-Sundia:
A. Utilize CRISPR technology to type the HiBiT small tag at the genome level use multiple methods to verify the correct tag of endogenous target protein at the gene and protein level establish sensitive and stable HiBiT cell strains that can be used for high-throughput screening and use positive compounds and negative compounds for end-point detection and real-time dynamic detection analyze data and unite different parameters. At the same time optimize other existing detection technologies for endogenous protein expression and use both advantages and disadvantages of various technologies to complete diversified detection of target protein degradation;
B. On the basis of NanoBRET principle establish relevant experiments to detect the membrane permeability of PROTAC compounds and the binding efficiency to intracellular protein use various extracellular biochemical experiments to evaluate the binding performance of PROTAC compounds to target protein and E3 ligase respectively so as to provide data support for the optimization of compound.
C. On the basis of NanoBRET principle establish relevant experiments to detect the formation ubiquitination and proteasome degradation of the intracellular target-PROTAC-E3 ligase ternary complex and develop the TR-FRET biochemical detection method for specific target so as to evaluate the performance of PROTAC compound and provide important data for the research and development of PROTAC.
D. Use synthesis methods to manufacture instrumental compounds in the chemistry department so as to verify and optimize the above-mentioned experimental platform.
E. Optimize and integrate existing detection techniques including expression level detection of intracellular protein intracellular and extracellular protein binding cell viability and other experiments so as to further display their values in the research and development of PROTAC.
F. Study the expression profiling of different E3 ligases in various tissues and tumors explore and discover new small molecule compounds that bind E3 ligases and provide new tools and directions for the research and development of PROTAC to break the bottleneck of existing tools .
Conclusion
The drug R&D and biology department of BioDuro-Sundia has developed rapidly since its establishment providing high-quality R&D services for many new drug R&D institutions and companies at home and abroad. Now more and more domestic and foreign research institutions and pharmaceutical companies have participated in the development of PROTAC. Many "undruggable" targets are yet to be developed into PROTAC new small molecule drugs. With its strong R&D capabilities and skills BioDuro-Sundia is committed to establish a one-stop PROTAC R&D platform and provide comprehensive and superior services to various new drug R&D companies.
BioDuro-Sundia will provide customers with complete services about comprehensive in vitro detection for PROTAC drugs build a one-stop detection platform complete various in vitro detection and evaluation services for PROTAC compounds and provide detailed data to support the further chemical optimization and upgrading of candidate compounds so as to provide comprehensive solutions of early research and development for many institutions that are dedicated to the research and development of PROTAC drugs.
About BioDuro-Sundia
BioDuro-Sundia an Advent International portfolio company is a leading contract research development and manufacturing organization (CRDMO) that provides biopharmaceutical partners with fully integrated services to support drug discovery development and manufacturing for both drug substance and drug product. The company is the industry's third largest with major operations in China and the US—featuring more than 2 000 employees and 10 global sites.
Core expertise includes small and large molecule discovery development and scale up support for IND submission and unique technology platforms such as bioavailability enhancement of insoluble compounds. The company has research sites as well as GMP manufacturing facilities in both China and the US. The one-stop-shop operation helps biopharma partners across the globe to significantly accelerate discovery and de-risk development to create higher value outcomes.
BioDuro-Sundia investment is led by Advent International with backing from Bridgewest Business Group.
About Advent International
Founded in 1984 Advent International is one of the largest and most experienced global private equity investors. The firm has invested in over 350 private equity transactions in 41 countries and as of June 30 2020 had $58.4 billion in assets under management. With 15 offices in 12 countries Advent has established a globally integrated team of over 200 investment professionals across North America Europe Latin America and Asia. The firm focuses on investments in five core sectors including business and financial services; health care; industrial; retail consumer and leisure; and technology. After 35 years dedicated to international investing Advent remains committed to partnering with management teams to deliver sustained revenue and earnings growth for its portfolio companies.
About Bridgewest Business Group
Founded in 1999 The Bridgewest Business Group is a closely held investment company that seeks to create long term value through application of superior industry knowledge operational expertise and significant financial resources to attractive investment opportunities. The Group structures its global investments across four functional areas including private equity real estate capital markets and financial services. The Group's private equity investments are primarily in biotech wireless communications infrastructure for IoT and semiconductor. Bridgewest is based in San Diego CA and has investments across the USA Europe Asia and Australasia.
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