同行致遠 | 攻克不可成藥，共價藥物帶動小分子藥物復興 | Bilingual

編者按：隨著研發技術的不斷進步，新一代共價藥物的開發已成為業界高度關注的方向。截至目前，已有超過50種共價藥物成功獲批上市，并在多個疾病領域展現出顯著療效。值得關注的是，新一代共價藥物正不斷突破局限，向可逆性共價結合及靶向半胱氨酸以外氨基酸殘基的方向快速拓展，為攻克“不可成藥”靶點帶來全新契機。依托端到端的CRDMO賦能平臺，藥明康德致力為全球合作伙伴提供覆蓋共價藥物發現與開發的一體化解決方案。本文將重點介紹藥明康德在共價藥物發現領域的技術與能力。

共價藥物作為現代藥物研發的重要方向，正在不斷拓展治療的邊界。早在上世紀，阿司匹林和青霉素的成功已充分證明了共價藥物在臨床中的重要價值。與傳統非共價抑制劑不同，共價藥物通過與靶點形成穩定的化學鍵，實現持久的抑制效果。憑借這一獨特機制，共價藥物不僅能夠以更低的劑量給藥，還可顯著提升靶點占有率，展現出極具潛力的廣闊臨床應用前景。

根據結合特性的不同，共價藥物可分為不可逆與可逆兩類：前者如青霉素，能夠形成長期抑制作用；后者如硼替佐米（bortezomib），在結合過程中仍具備一定的可逆性，從而兼具療效的持續性與可調控性。在過去十年里，共價藥物進入了快速發展階段。截至2024年，已有超過50款共價藥物獲FDA批準上市。這些藥物已廣泛應用于癌癥、病毒感染、遺傳性疾病及心血管疾病等多個治療領域。其中，BTK抑制劑伊布替尼（ibrutinib）與EGFR抑制劑阿法替尼（afatinib）是首批通過理性設計問世的共價抑制劑。它們的成功不僅再次證明了共價結合的臨床潛力，也確立了一種重要的開發策略——在已有可逆性結合分子的骨架上，引入能夠與靶點形成共價鍵的化學基團，從而顯著增強藥物活性與選擇性。

在這一策略之外，KRAS G12C抑制劑sotorasib和adagrasib的誕生，展現了共價藥物研發理念轉變的臨床實踐。面對長期被視為“不可成藥”的KRAS靶點，研究人員突破性地采用直接篩選策略，尋找能夠與KRAS突變體半胱氨酸快速形成共價鍵的小分子化合物。這一方法不同于以往依賴修飾現有非共價分子的模式，而是開創性地針對全新靶點的突變位點進行共價結合與優化，最終推動了首批KRAS靶向療法的問世，標志著共價藥物研發正從傳統分子改造邁向更具前瞻性的靶點創新。

與此同時，新一代共價藥物在提升選擇性的同時，其研發也正逐步拓展至更廣泛的靶點范圍。傳統聚焦于半胱氨酸的策略，正逐步拓展至賴氨酸、絲氨酸、蘇氨酸及酪氨酸等非半胱氨酸殘基，并通過引入新型共價彈頭（warhead）結構，實現更高的特異性與更低的脫靶風險。這一創新路徑不僅有望進一步提升藥物的安全性和療效，也為眾多長期被視為“難以成藥”的靶點開辟了全新解決方案，從而為更多疾病患者帶來切實的臨床獲益。

為幫助全球合作伙伴加速下一代共價藥物的研發——從早期發現到IND申報，藥明康德建立了一體化發現平臺。該平臺融合了三大互補技術：共價DNA編碼化合物庫（cDEL）、共價片段藥物發現（cFBDD）以及共價高通量篩選（cHTS），為共價藥物發現提供了高效的解決方案。

▲藥明康德共價藥物發現能力

cDEL是一項功能強大的篩選技術，能夠高效探索龐大的化學空間，大幅提升發現多樣化共價分子及其結合彈頭的可能性。通過將DNA標簽作為“分子條形碼“，該平臺可在僅需極少量蛋白和化合物的條件下，實現快速且具成本效益的苗頭化合物發現，在化學多樣性至關重要的早期研發階段尤為突出。憑借靈活的篩選策略，藥明康德的cDEL平臺擁有可逆與不可逆的共價結合物庫，篩選后通過測序解碼、再合成以及嚴格的DNA連接與非DNA連接檢測方法進行系統驗證。為滿足不同合作伙伴的研發需求，藥明康德提供兩種不可逆共價藥物篩選模式：DELink Pro——涵蓋16億化合物和184種專門設計的共價彈頭，并提供獨特且可定制的一步式解決方案；以及DELinkLite——包含超過1400萬化合物的精簡平臺，可為客戶提供更便捷的數據獲取與利用。

▲藥明康德共價DEL庫介紹

藥明康德的cFBDD平臺基于一個經過嚴格篩選的化合物庫，包含超過2600個結構多樣化的片段，每個片段均按照“三規則”設計（即藥物片段的分子量應不超過300 Da，cLogP不大于3，且氫鍵供體或受體的數量不超過3，以確保其分子保持小巧、具備良好溶解性），以確保理化性質與化學多樣性的優化。該平臺以小而低復雜度的分子片段為核心，高效探索結合位點，并通過引入帶有親電基團的片段，快速識別可作為優化起點的共價結合物。結合高通量質譜以及X射線晶體學、核磁共振（NMR）等結構生物學方法，cFBDD能夠在原子水平提供片段–蛋白相互作用的深度洞察，從而支持理性設計與系統優化。該片段庫無化學反應性與穩定性問題，且具備良好的可合成性。憑借結構精度、快速周期與高效的苗頭至先導化合物轉化，cFBDD已成為推動新型共價先導分子的重要工具，尤其適用于挑戰性靶點或傳統意義上“不可成藥”的靶點。

▲共價片段藥物發現平臺篩選流程

藥明康德的cHTS平臺是集合了藥明康德cHTS共價庫和多種篩選方法的高通量篩選平臺。藥明康德的cHTS共價庫約有6萬9千個分子，涵蓋50多種不同類型的共價彈頭，反應活性范圍多樣。這些化合物能夠作用于九類不同的氨基酸殘基，將共價藥物發現的范圍從半胱氨酸擴展至絲氨酸、賴氨酸以及其他殘基專屬的化合物庫。由于這些替代性殘基在蛋白中更為豐富，并具備環境特異性的反應活性，該化合物庫不僅能夠拓展潛在的治療靶點空間，還有望提升藥物選擇性并減少脫靶作用。

cHTS平臺可以提供多種篩選方法：作為共價藥物發現中最成熟的方法之一，功能性實驗支持的高通量篩選能夠直接在酶學或細胞系統中測試大量含親電基團的分子，快速生成功能性數據，以確認化合物的真實抑制活性。同時高通量質譜篩選可以快速直接檢出靶點分子量位移，以確認化合物的實際結合。這確保了所識別的苗頭化合物具備下游優化和臨床開發的理想特性，為后續藥物研發奠定堅實基礎。同時藥明康德的cHTS平臺提供多種正交苗頭化合物驗證，可以為從苗頭到先導保駕護航。整合了高通量化學的cHTS平臺同時提供D2B解決方案。D2B解決方案包括了快速合成和快速檢測，為苗頭化合物擴展提供支持。藥明康德的cHTS共價平臺不只是一個單一的篩選平臺，而是同時可以為苗頭化合物發現和從苗頭到先導提供全方位支持。

▲藥明康德共價HTS庫介紹

除了作為抑制劑之外，共價藥物也在新興療法中展現出日益廣闊的應用前景，尤其是在誘導鄰近（induced proximity）領域。例如，通過發現能夠作用于E3泛素連接酶的共價招募分子，研究人員有望進一步拓展靶向蛋白降解（TPD）的作用范圍。與此同時，針對OTUB1的共價招募分子的發現，推動了去泛素化酶靶向嵌合體（DUBTAC）平臺的建立，該平臺能夠穩定囊性纖維化（CF）患者中的突變型CFTR蛋白，從而為這一嚴重遺傳疾病提供了全新的治療方向?？梢姡?strong>共價分子的應用價值已遠不止于抑制作用，而是逐漸延伸至多維度的治療策略，為創新藥物研發開辟了更廣闊的發展空間。

在共價藥物篩選平臺之外，藥明康德還建立了一整套早期藥物發現技術平臺，涵蓋生物物理學、生物化學及細胞學檢測，為全球合作伙伴共價藥物的開發提供堅實的支持。依托端到端的一體化CRDMO賦能平臺，藥明康德致力于加速突破性療法的開發，幫助合作伙伴將創新成果高效轉化為造福全球患者的解決方案，以踐行“讓天下沒有難做的藥，難治的病”的愿景。

Redefining the Undruggable: Covalent Therapies Driving a New Era for Small Molecules

With advances in biopharmaceutical research and development, next-generation covalent drugs have emerged as a major focus across the industry. To date, more than 50 covalent drugs have been approved for clinical use, demonstrating substantial value across a broad range of therapeutic areas. Importantly, these next-generation therapies are advancing toward reversible covalent binding and targeting amino acid residues beyond cysteine, thereby opening new possibilities for addressing previously “undruggable” targets. Leveraging its fully integrated, end-to-end CRDMO enabling platform, WuXi AppTec provides global partners with comprehensive solutions for covalent drug discovery and development. This article highlights WuXi AppTec’s capabilities and strengths in enabling innovation in covalent drug discovery.

Covalent drugs have become a powerful force in modern drug discovery, continuously expanding the boundaries of therapeutic innovation. As early as the last century, aspirin, with its well-recognized anti-inflammatory and analgesic effects, and penicillin, the first antibiotic effective against a wide range of bacterial infections, demonstrated the immense clinical value of covalent interactions.Unlike traditional non-covalent inhibitors, covalent drugs form stable chemical bonds with their targets, enabling durable inhibition.This unique mechanism allows for lower dosing requirements and higher target occupancy, underscoring their broad potential in clinical applications.

Based on their binding characteristics, covalent drugs can be classified into irreversible and reversible categories.Irreversible inhibitors, such as penicillin, provide long-lasting suppression, while reversible covalent drugs like bortezomib retain a degree of flexibility, balancing durability with tunability. Over the past decade, covalent drugs have entered a phase of rapid growth. By 2024, more than 50 covalent drugs had been approved for clinical use across a wide range of therapeutic areas, including oncology, infectious diseases, genetic disorders, and cardiovascular conditions. Among them, ibrutinib (a BTK inhibitor) and afatinib (an EGFR inhibitor) were the first rationally designed covalent inhibitors.Their success not only reaffirmed the clinical value of covalent bonding but also established a key development strategy: introducing covalent warheads into reversible scaffolds to significantly enhance potency and selectivity.

Beyond this strategy, the approval of KRAS G12C inhibitors sotorasib and adagrasib represents a landmark in the clinical application of a new paradigm in covalent drug discovery. Confronting KRAS—a target long regarded as “undruggable”—researchers adopted a direct-screening strategy to identify small molecules capable of rapidly forming covalent bonds with the mutant cysteine residue. Unlike traditional approaches that relied on modifying existing non-covalent scaffolds,this method focused directly on the mutation site to achieve covalent binding and the optimization of molecules against a new target.This signaled a forward-looking shift in covalent drug discovery from conventional molecular modification to innovative, target-driven design.

At the same time, next-generation covalent drugs are progressing rapidly toward improved selectivity. In parallel, they are being developed to address an increasingly broad spectrum of therapeutic targets. While earlier strategies largely focused on cysteine residues,new approaches are expanding to lysine, serine, threonine, and tyrosine. By incorporating novel covalent warhead chemistries, these strategies aim to achieve higher specificity with reduced off-target risk.This innovative path not only promises to improve the safety and efficacy of covalent therapies but also offers new solutions for protein targets once deemed intractable—ultimately delivering tangible clinical benefits to patients across a wide range of diseases.

To help global partners accelerate the development of next-generation covalent drugs, from early discovery through IND-enabling studies, WuXi AppTec has established an integrated platform.By combining three complementary, state-of-the-art technologies—covalent DNA-Encoded Library (cDEL), covalent Fragment-Based Drug Discovery (cFBDD), and covalent High-Throughput Screening (cHTS)—the platform provides a highly efficient solution to advance covalent drug discovery.

▲WuXi AppTec’s capabilities in covalent drug discovery

cDEL is a powerful screening technology that enables the efficient exploration of vast chemical libraries, greatly increasing the likelihood of identifying covalent binders with diverse warheads.Leveraging DNA tags as molecular barcodes, the platform allows rapid and cost-effective deconvolution of hits while requiring only minimal quantities of protein and compound.This makes it particularly valuable in the early discovery stage, where broad chemical diversity is essential.Through tailored selection strategies, WuXi AppTec’s cDEL platform uncovers both reversible and irreversible covalent hits, which are further validated through decoding, resynthesis, and rigorous on-DNA and off-DNA assays.To meet diverse partner needs, WuXi AppTec offers two models for irreversible covalent drug screening: DELink Pro, an exclusive, customizable solution featuring a comprehensive library of 1.6 billion compounds and 184 specialized warheads; and DELink Lite, a streamlined option with more than 14 million compounds that provides clients with enhanced access to screening data.

▲Introduction of WuXi AppTec's cDEL

WuXi AppTec’s cFBDD platform builds on a rigorously curated library of more than 2,600 structurally diverse fragments, each designed under the “rule of three (Ro3)” to ensure optimal physical properties and chemical diversity.(Ro3 holds that drug fragments should be ≤300 Da, cLogP ≤3, and carry no more than 3 hydrogen bond donors or acceptors to remain small, soluble, and readily optimized.)By focusing on small, low-complexity molecules, the platform efficiently probes binding sites and, through the incorporation of electrophilic fragments, identifies covalent hits that serve as highly effective starting points for optimization.Leveraging high-throughput mass spectrometry together with structural biology methods such as X-ray crystallography and NMR,cFBDD provides atomic-level insights into fragment–protein interactions, enabling rational design and systematic growth of covalent inhibitors.The fragment library is free from reactivity and stability issues, remains synthetically accessible, and delivers high-quality data with speed and precision. The combination of structural precision, rapid turnaround, and efficient hit-to-lead progression makes cFBDD a powerful approach for advancing novel covalent leads, particularly against the most challenging or traditionally “undruggable” targets.

▲Covalent FBDD workflow

The cHTS platform from WuXi AppTec is a platform that incorporates various screening strategies.The covalent HTS library has approximately 69,000 covalent molecules featuring more than 50 distinct warhead chemotypes across a range of reactivities. Our library is purpose-built to engage with nine different amino acid residues, extending covalent drug discovery beyond cysteine to include serine-, lysine-, and other residue-focused libraries. Because these alternative residues are more abundant in proteins and exhibit environment-specific reactivity, the platform provides access to previously undruggable proteins while improving selectivity and reducing off-target interactions.

The cHTS platform provides different screening methods.The functional-assay-based high-throughput screening, as one of the most established approaches in covalent drug discovery, can test extensive collections of electrophile-containing molecules directly in enzymatic or cellular systems; Mass-Spectrometry-based high-throughput screening can test the molecular weight shifter upon covalent drug binding. These enable rapid generation of functional readouts or mass readouts that confirm actual inhibitory or binding activity, ensuring identification of hits that possess favorable properties for further optimization and clinical development. The cHTS platform can also provide a wide variety of assay for orthogonal hit confirmation, which can transfer the screening hits to confirmed hits. By integrating High-Throughput Chemistry (HTC), the cHTS platform offers a D2B solution that unites fast synthesis and quick-turnaround testing to speed hit expansion.More than a screening engine, cHTS supports the full workflow from Hit ID through Hit-to-Lead.

▲WuXi AppTec’s covalent compound library

Beyond functioning as inhibitors, covalent drugs are demonstrating increasingly broad potential in emerging therapeutic approaches, particularly in the field of induced proximity. For example, the discovery of covalent recruiters for E3 ubiquitin ligases has the potential to expand the scope of targeted protein degradation (TPD). At the same time, the identification of covalent recruiters for OTUB1 has led to the development of the deubiquitinase-targeting chimera (DUBTAC) platform, which can stabilize mutant CFTR proteins in patients with cystic fibrosis (CF), offering a new therapeutic direction for this severe genetic disease. Therefore,the value of covalent molecules extends far beyond inhibition, gradually evolving into multidimensional therapeutic strategies that open broader possibilities for innovative drug discovery.

Complementing its advanced screening capabilities,WuXi AppTec offers a comprehensive suite of early discovery technology platforms—including biophysical, biochemical, and cellular assays—to support global partners in advancing covalent drug development.Backed by an integrated, end-to-end CRDMO enabling platform, WuXi AppTec is committed to accelerating the development of transformative therapies that deliver meaningful benefits to patients worldwide—fulfilling its vision that “Every drug can be made and every disease can be treated.”

參考資料:

[1] Discovery of a Novel Covalent Inhibitor using DNA Encoded Library. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202208

[2] Progressive Covalent DEL in WuXi. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202205

[3] Covalent Drug Discovery. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202180

[4] 百年應用歷史卻被“有意回避”，這種藥物開發策略如今能攻克不可成藥靶點嗎？Retrieved August 18, 2025, from https://mp.weixin.qq.com/s?__biz=MzAwMDA5NTIxNQ==&mid=2650031219&idx=1&sn=5bc46ed3b8cbcaeb66f8d9fea5753b4b&chksm=82eec2f3b5994be5fa330dd8dd877cd24597710394dfdc248a5f0a3466e08493b26b9c94bcab

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[6] Hameed et al., (2024). Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review. European Journal of Medicinal Chemistry Reports, https://doi.org/10.1016/j.ejmcr.2024.100217

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