從400億分子中鎖定成藥潛力！藥明康德一體化平臺拓展靶向蛋白降解研發(fā)邊界 | Bilingual

編者按：近年來，新興療法持續(xù)涌現(xiàn)，重新定義了藥物發(fā)現(xiàn)的傳統(tǒng)邊界。作為其中的前沿代表，靶向蛋白降解（TPD）療法已經(jīng)成為新藥研發(fā)的熱點。這類可從源頭降解致病蛋白的療法，有望靶向許多長期被認(rèn)為“不可成藥”的靶點。早在TPD技術(shù)興起之初，藥明康德就前瞻性地布局了相關(guān)能力和技術(shù)，搭建了集發(fā)現(xiàn)、合成、分析純化和測試等能力于一體的一體化賦能平臺。本文將結(jié)合藥明康德生物學(xué)業(yè)務(wù)平臺團隊在美國癌癥研究協(xié)會（AACR）年會展示的案例，介紹其一體化發(fā)現(xiàn)平臺如何高效助力TPD潛力分子的發(fā)現(xiàn)。

在不久前的2026年美國癌癥研究協(xié)會（AACR）年會上，靶向蛋白降解（TPD）療法無疑是備受矚目的領(lǐng)域之一。其中，從CRBN、VHL等傳統(tǒng)E3泛素連接酶向更多新型酶的拓展，成為值得關(guān)注的新興趨勢。在這一領(lǐng)域，藥明康德生物學(xué)平臺團隊在現(xiàn)場通過壁報展示了兩項研究進展。

在其中一項研究中，藥明康德生物學(xué)平臺構(gòu)建了全新的分子膠庫，并篩選鑒定出超過100個苗頭化合物，其中包含了不依賴于傳統(tǒng)E3連接酶CRBN的分子，為非CRBN類分子膠及新型TPD策略的開發(fā)提供了全新路徑。

另一項研究則利用DNA編碼化合物庫（DEL）篩選，探索了新型E3連接酶，并構(gòu)建了一系列靶向目標(biāo)蛋白BRD4的蛋白降解靶向嵌合體分子，驗證了DEL技術(shù)在新型E3連接酶及TPD療法開發(fā)中的作用。

那么，開發(fā)新型E3連接酶為何如此關(guān)鍵？這要從TPD類分子的作用機制說起。

一體化發(fā)現(xiàn)平臺應(yīng)對TPD挑戰(zhàn)

以蛋白降解靶向嵌合體、分子膠為代表的TPD療法，巧妙地利用了人體內(nèi)泛素介導(dǎo)的蛋白降解系統(tǒng)，實現(xiàn)對目標(biāo)蛋白的選擇性降解。

這些TPD分子招募的關(guān)鍵酶，正是E3連接酶。在泛素化過程中，E3連接酶負(fù)責(zé)識別底物蛋白，并將代表著“待降解”的泛素標(biāo)簽貼到目標(biāo)蛋白上。因此，E3連接酶在很大程度上決定了降解的選擇性與效率。

人類編碼的E3連接酶數(shù)量超過600種，但絕大多數(shù)都缺乏已知可用的配體。目前在TPD藥物開發(fā)中，得到廣泛應(yīng)用的僅有CRBN和VHL等少數(shù)幾種傳統(tǒng)E3連接酶。這不僅限制了化學(xué)空間的拓展，也可能導(dǎo)致耐藥性風(fēng)險。

因此，如何系統(tǒng)性地挖掘非傳統(tǒng)的E3連接酶并發(fā)現(xiàn)相應(yīng)的小分子配體，成為當(dāng)前TPD領(lǐng)域亟待突破的方向。

圍繞TPD藥物發(fā)現(xiàn)，藥明康德生物學(xué)平臺構(gòu)建了覆蓋靶點驗證、分子發(fā)現(xiàn)與功能機制解析的系統(tǒng)化一體化發(fā)現(xiàn)平臺，能夠有效應(yīng)對異雙功能分子、分子膠類等藥物在早期研發(fā)階段面臨的復(fù)雜生物學(xué)挑戰(zhàn)。

該平臺支持TPD領(lǐng)域從活性化合物篩選、評估優(yōu)化、候選化合物篩選等多階段的研究。其中，篩選平臺整合了DNA編碼化合物庫、片段篩選、親和選擇質(zhì)譜（ASMS）及虛擬篩選等多種技術(shù)手段，用于高效識別靶蛋白配體與E3連接酶配體，并支持新型連接子設(shè)計與復(fù)雜雙功能分子的優(yōu)化。

從海量分子中“釣”出潛力配體

以借助DEL篩選新型E3連接酶的壁報為例，研究團隊使用篩選平臺中的DEL技術(shù)，從30個候選E3連接酶出發(fā)，對超過400億化合物的化學(xué)空間進行了系統(tǒng)性的親和力篩選與評估。

在這一過程中，一個名為GID4的候選蛋白脫穎而出。

GID4是CTLH E3泛素連接酶復(fù)合物中的底物識別亞基，負(fù)責(zé)識別、招募需要降解的目標(biāo)蛋白。已經(jīng)有研究發(fā)現(xiàn)，GID4能夠在細胞內(nèi)靶向異位招募的底物并介導(dǎo)其降解，其作為蛋白降解靶向嵌合體E3連接酶的潛力也得到證實。

通過對超過400億分子的DEL篩選，研究團隊獲得了3個系列與GID4有不同親和力的苗頭化合物。但最初的苗頭化合物分子量大，并且配體結(jié)合率低，限制了其作為結(jié)合配體開發(fā)TPD分子的能力。

面對挑戰(zhàn)，研究團隊首先通過對初始苗頭化合物系統(tǒng)的截短和片段化，分析結(jié)合力測試數(shù)據(jù)與配體結(jié)合率指標(biāo)，來確定關(guān)鍵藥效團的特征。然后基于片段化分子，團隊通過配體生長方法設(shè)計和分子模擬的方法進一步優(yōu)化結(jié)構(gòu)，成功發(fā)現(xiàn)了分子量低于400、結(jié)合力、配體結(jié)合效率高的潛力GID4配體分子。

隨后，為了驗證GID4配體能否開發(fā)為TPD分子，團隊將其中一個優(yōu)化的GID4配體和BRD4蛋白配體連接，快速構(gòu)建了蛋白降解靶向嵌合體，驗證了這些TPD分子能夠誘導(dǎo)三元復(fù)合物的形成，并成功降解目標(biāo)蛋白BRD4。

完成初步驗證后，研究團隊需要進一步探索GID4配體，BRD4配體和連接子的最優(yōu)連接方式。然而蛋白降解靶向嵌合體的優(yōu)化往往缺少理性設(shè)計，在傳統(tǒng)藥物發(fā)現(xiàn)流程中需要花費大量的人力和物力。

在此階段，藥明康德團隊的Direct-to-Biology（D2B）平臺成為關(guān)鍵引擎，強力驅(qū)動靶向蛋白降解藥物分子的開發(fā)。D2B策略通過在微孔板中進行納摩爾級的高通量化學(xué)反應(yīng)，直接在微孔板中批量合成化合物并緊接著用于生物測試，在顯著減少原料和試劑投入的同時，僅需2-3周時間就可以完成上千個化合物的設(shè)計、合成、測試以及初篩結(jié)果分析，極大縮短了藥物研發(fā)周期。

基于該策略，研究團隊從內(nèi)部研發(fā)優(yōu)化的近10個GID4優(yōu)質(zhì)配體出發(fā)，充分考慮連接子結(jié)構(gòu)多樣性，通過組合化學(xué)設(shè)計系統(tǒng)性探索構(gòu)效關(guān)系（SAR）信息和最優(yōu)的組合方式。

利用D2B平臺，團隊在兩周內(nèi)高效完成上百個衍生分子的合成與篩選，獲得SAR信息的同時，快速鎖定幾個以GID4為E3泛素連接酶受體，表現(xiàn)更優(yōu)的蛋白降解靶向嵌合體分子，其BRD4降解活性較初始苗頭化合物提升10倍，為后續(xù)開發(fā)奠定了堅實基礎(chǔ)。

▲D2B策略為SAR研究提供支持，并加速了蛋白降解靶向嵌合體分子的優(yōu)化進程（圖片來源：藥明康德生物學(xué)平臺）

“正如本次AACR會議所呈現(xiàn)的趨勢，TPD的研究范圍正從依賴少數(shù)經(jīng)典E3連接酶，向著更多元的新型E3連接酶體系拓展，這一轉(zhuǎn)變對藥物發(fā)現(xiàn)能力提出了更高的要求，”藥明康德研發(fā)生物學(xué)平臺負(fù)責(zé)人、生物學(xué)業(yè)務(wù)平臺能力中心負(fù)責(zé)人蘇文姬博士指出，“圍繞TPD分子的研發(fā)需求，藥明康德構(gòu)建的一體化發(fā)現(xiàn)平臺整合了多樣化的篩選技術(shù)，同時提供D2B解決方案，能夠在更復(fù)雜的化學(xué)空間中高效識別并優(yōu)化新型E3連接酶配體，加速TPD療法的創(chuàng)新進程。”

TPD崛起：從機制突破到臨床加速

過去十年間，TPD療法迅速崛起，研發(fā)管線持續(xù)擴展，覆蓋癌癥、免疫性疾病、神經(jīng)退行性疾病等多個領(lǐng)域。例如，靶向降解雌激素受體（ER）的蛋白降解靶向嵌合體Veppanu（vepdegestrant）不久前獲美國FDA批準(zhǔn)上市，為攜帶ESR1突變的HR+/HER2-乳腺癌患者提供新療法；新一代分子膠iberdomide同樣有望在今年完成FDA審評，用于復(fù)發(fā)或難治性多發(fā)性骨髓瘤。

TPD療法的廣闊前景也吸引了資本的高度關(guān)注。就在近期，致力于開發(fā)分子膠降解劑的生物技術(shù)公司Neomorph宣布完成1億美元B輪融資，用于推進在研分子膠降解劑NEO-811的1/2期臨床試驗。

由于結(jié)構(gòu)復(fù)雜、分子量較大，這些傳統(tǒng)意義上“難以成藥”的TPD分子對平臺能力提出了更高的要求。

早在2016年，TPD領(lǐng)域的研發(fā)剛剛起步，藥明康德就前瞻性地布局了相關(guān)能力和技術(shù)，搭建了集發(fā)現(xiàn)、合成、分析純化和測試等能力于一體的一體化賦能平臺。伴隨著新型TPD分子的涌現(xiàn)，平臺技術(shù)的能力已涵蓋蛋白降解靶向嵌合體、調(diào)節(jié)誘導(dǎo)接近靶向嵌合體、分子膠、自噬靶向嵌合體、溶酶體靶向嵌合體、去泛素化酶靶向嵌合體、核糖核酸酶靶向嵌合體、磷酸化誘導(dǎo)嵌合小分子以及抗體偶聯(lián)降解劑等主要分子類型。

展望未來，隨著更多沉睡的E3連接酶被激活，TPD療法的版圖也將進一步擴展，一個更廣闊的藥物研發(fā)空間，正在逐漸顯現(xiàn)。

在這段旅途中，藥明康德將持續(xù)以一體化、端到端的CRDMO賦能平臺，助力全球合作伙伴加速TPD等創(chuàng)新療法的研發(fā)生產(chǎn)進程，讓科學(xué)突破更快為患者帶來福祉。

From 40 Billion Molecules to Druggable Potential: WuXi AppTec's Integrated Platform Expands the Boundaries of Targeted Protein Degradation

At the American Association for Cancer Research (AACR) Annual Meeting 2026, targeted protein degradation (TPD) therapies were among the most prominent areas of focus. In particular,the expansion from traditional E3 ligases such as CRBN and VHL to a broader range of novel ligases has emerged as a noteworthy trend.In this field, the WuXi Biology team of WuXi AppTec presented two research updates via posters at the conference.

In one of these studies,WuXi Biology constructed a novel molecular glue library and identified over 100 hit compounds, including CRBN-independent candidates. This work provides a new path for the development of non-CRBN molecular glues and next-generation TPD strategies.

In the other study,the team leveraged DEL screening to explore novel E3 ligases and constructed a series of proteolysis-targeting chimeras targeting the protein BRD4, demonstrating the value of DEL technology in the discovery of novel E3 ligases and the development of TPD therapies.

Why is the development of novel E3 ligases so critical? The answer lies in the mechanism of action of TPD molecules.

An Integrated Discovery Platform to Address TPD Challenges

TPD therapies, represented by proteolysis-targeting chimeras and molecular glues, harness the ubiquitin-mediated protein degradation system within the human body to achieve selective degradation of target proteins.

The key enzymes recruited by these TPD molecules are E3 ligases.In the ubiquitination process, E3 ligases are responsible for recognizing substrate proteins and tagging them with ubiquitin, effectively marking them for degradation. As such,E3 ligases largely determine the selectivity and efficiency of protein degradation.

Humans encode more than 600 E3 ligases, yet the vast majority lack known, tractable ligands. Currently, only a few traditional E3 ligases, such as CRBN and VHL, are widely used in TPD drug development. This not only limits the expansion of chemical space but may also introduce risks of drug resistance.

Therefore,systematically exploring non-traditional E3 ligases and discovering corresponding small-molecule ligands has become a key challenge for the TPD field.

To support TPD drug discovery, WuXi Biology has built a systematic, integrated discovery platform covering target validation, molecule discovery, and functional mechanism characterization. The platform is designed to address the complex biological challenges associated with bifunctional degraders, molecular glues and other therapeutics in early-stage drug discovery.

The platform supports multiple stages of research in the TPD field, including hit finding, hit triage, and candidate selection. Its screening capabilities integrate multiple advanced ligand discovery strategies, including DNA-encoded library (DEL) screening, fragment-based approaches, affinity selection mass spectrometry (ASMS), and virtual screening, enabling efficient identification of both target protein ligands and E3 ligase ligands. In addition, it supports the design and optimization of novel linkers and complex bifunctional molecules.

“Fishing” for Potential Ligands from Vast Chemical Space

Taking the poster on discovering novel E3 ligases via DEL screening as an example,the research team utilized DEL technology within the screening platform to conduct systematic affinity selection and evaluation across a chemical space of more than 40 billion compounds, across 30 candidate E3 ligases.

Through this process, a candidate protein named GID4 stood out.

GID4 is a substrate-recognition subunit of the CTLH E3 ligase complex, responsible for recognizing and recruiting target proteins for degradation. Previous studies have shown that GID4 can mediate the degradation of recruited substrates, highlighting its potential as an E3 ligase component for proteolysis-targeting chimeras.

Through DEL screening of more than 40 billion compounds, the team identified three hit series with varying affinities for GID4.However, the initial hits were characterized by high molecular weight and low ligand efficiency, limiting their potential as ligands for TPD molecule development.

To address these challenges, the team first applied systematic truncation and fragmentation of the initial hits, analyzing binding affinity alongside ligand efficiency metrics to define key pharmacophoric features. Building on these fragments, they then further refined the structures, ultimately identifying a set of promising GID4 ligands with molecular weights below 400 and significantly improved binding affinity and ligand efficiency.

To validate whether these GID4 ligands could be developed into TPD molecules, the team conjugated one optimized GID4 ligand to a BRD4-binding moiety to rapidly construct proteolysis-targeting chimeras. These molecules induced ternary complex formation and successfully degraded the target protein BRD4.

Following the initial validation, further exploration was needed to optimize the combination of GID4 ligands, BRD4 ligands, and linker designs. However, optimization of proteolysis-targeting chimeras often lacks rational design and is resource-intensive in traditional drug discovery workflows.

At this stage, WuXi AppTec’s Direct-to-Biology (D2B) platform became a critical engine that accelerated the development of targeted protein degradation molecules.By enabling nanomole-scale, high-throughput chemical synthesis directly in microplates, followed immediately by biological testing, the D2B approach allows for rapid design, synthesis, testing, and preliminary analysis of thousands of compounds within just 2-3 weeks, while significantly reducing material and reagent consumption.

Leveraging this strategy, the team started with nearly ten internally optimized, high-quality GID4 ligands and systematically explored linker diversity. Through combinatorial chemistry design, they efficiently mapped structure–activity relationships (SAR) and identified optimal combinations of ligands and linkers.

Using the D2B platform, the team synthesized and screened hundreds of derivatives within two weeks, rapidly identifying several GID4-recruiting proteolysis-targeting chimeras with superior degradation activity. These molecules demonstrated a tenfold improvement in BRD4 degradation activity compared with the initial hits, laying a solid foundation for further development.

▲The D2B strategy supports SAR studies and accelerates the optimization of proteolysis-targeting chimera molecules(Image source: WuXi Biology)

“As highlighted at this year’s AACR meeting, the field of TPD is rapidly expanding beyond a handful of classical E3 ligases into a more diverse and complex landscape of novel ligases, raising the bar for drug discovery capabilities,” noted Dr. Wenji Su, Head of Discovery Biology Platform at WuXi AppTec, “WuXi AppTec has established an integrated discovery platform for TPD, bringing together diverse screening technologies with Direct-to-Biology (D2B) solutions. This platform enables the efficient identification and optimization of novel E3 ligase ligands within increasingly complex chemical space, accelerating the innovation of TPD therapeutics.”

The Rise of TPD: From Mechanistic Breakthroughs to Clinical Acceleration

Over the past decade, TPD therapies have risen rapidly, with expanding pipelines spanning oncology, immune diseases, neurodegenerative disorders, and beyond. For example, the proteolysis-targeting chimera Veppanu (vepdegestrant) targeting the estrogen receptor (ER) was recently approved by the U.S. FDA, offering a new treatment option for patients with ESR1-mutant HR+/HER2- breast cancer. Another next-generation molecular glue, iberdomide, is also expected to complete FDA review this year for relapsed or refractory multiple myeloma.

The strong promise of TPD therapies has also attracted significant investor interest. Recently, Neomorph announced the completion of a $100 million Series B financing round to advance its molecular glue degrader NEO-811 into Phase 1/2 clinical trials.

Due to their structural complexity and relatively large molecular weight, these traditionally “undruggable” TPD molecules place higher demands on platform capabilities.

As early as 2016, when TPD research was still in its early stage, WuXi AppTec had already made forward-looking investments in this field, establishing an integrated enabling platform that combines discovery, synthesis, analytical purification, and testing capabilities. With the emergence of new TPD modalities, the platform now supports a broad range of molecular types, including proteolysis-targeting chimeras, regulated induced proximity targeting chimeras, molecular glues, autophagy-targeting chimeras (AUTACs), lysosome-targeting chimeras (LYTACs), deubiquitinase-targeting chimeras (DUBTACs), ribonuclease-targeting chimeras (RIBOTACs), phosphorylation-inducing chimeric small molecules (PHICS), and degrader-antibody conjugates (DAC).

Looking ahead, as more previously untapped E3 ligases are unlocked, the landscape of TPD therapies will continue to expand, revealing an increasingly vast space for drug discovery.

Throughout this journey, WuXi AppTec will continue to enable global customers with its integrated, end-to-end CRDMO platform, accelerating the development and manufacturing of innovative therapies such as TPD, and helping customers accelerate drug development for patients worldwide.

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