頂住非議20多年，耶魯教授把“夢中的療法”推向獲批上市后，又有新思路 | bilingual

多年以后，看著密封在塑料袋中的5公斤淺色藥物粉末，克雷格·克魯斯（Craig Crews）教授回想起上世紀90年代末那個遙遠的下午。當時，幾乎無人駐足觀看他的學術(shù)海報。

好在他并不孤單。這些海報是按姓氏首字母順序排列的，在他旁邊展出科研成果的，是一位名為雷蒙德·德沙耶（Raymond Deshaies）的年輕科學家。幾小時過去，駐足提問的參會者寥寥無幾，兩人便開始攀談起來。

那時的克魯斯還是耶魯大學的一名助理教授，他正如癡如醉地思考著一個不同尋常的化學構(gòu)想：一種異雙功能分子，能夠把細胞內(nèi)的兩個蛋白質(zhì)連接到一起。把它們拉得足夠近，或許就能讓它們發(fā)生相互作用。

德沙耶則是加州理工學院的酵母遺傳學家，多年來一直致力于研究調(diào)控細胞周期的機制。1997年，他的實驗室鑒定出一種被稱為SCF的蛋白復合體，它是精密的蛋白酶體通路的一部分。蛋白酶體通路即細胞內(nèi)部的“廢品處理系統(tǒng)”，負責識別和降解多余的蛋白質(zhì)。

兩位科學家開始好奇：

如果有一種分子把這兩種機制結(jié)合起來，會是什么樣？

如果有一種藥物，能在物理上將致病蛋白直接“拉”到細胞自身的降解系統(tǒng)面前，并把它標記為“垃圾”以供銷毀，會發(fā)生什么？

畢竟，當今的藥物大多建立在“抑制”的基礎(chǔ)上：阻斷蛋白質(zhì)的活性、關(guān)閉某些功能、抑制信號傳導。但這個設(shè)想截然不同，它構(gòu)想出了一種能讓整個問題蛋白消失無蹤的藥物。

“幾杯啤酒下肚后，我們開始討論如何利用異雙功能分子來‘劫持’蛋白酶體降解系統(tǒng)，”克魯斯后來回憶道，“那真是一個開創(chuàng)性的時刻。”

二十多年后，當年那場深夜對談萌生的想法，最終促成了首款獲FDA批準上市的蛋白降解靶向嵌合體療法問世，也推開了那扇通往一類全新藥物的大門——這類藥物設(shè)計的目的不再僅僅是抑制致病蛋白，而是把它們從細胞中“粉碎刪除”。

圖片來源：123RF

諾貝爾獎

令克魯斯和德沙耶著迷的設(shè)想，建立在精巧的細胞內(nèi)部清理系統(tǒng)之上。在人體細胞中，存在著上萬個、甚至上百萬個蛋白酶體，這種桶狀的分子結(jié)構(gòu)功能如同高度精密的“垃圾回收站”。它們的工作必不可少，盡管有些冷酷無情：識別出那些不需要的、受損或過剩的蛋白質(zhì)，并將其分解為可循環(huán)利用的片段。

但這個“垃圾處理系統(tǒng)”并不是不加選擇地進行清理。細胞承受不起隨意破壞蛋白質(zhì)的代價；要維系生存，就要精準地知道哪些蛋白質(zhì)應(yīng)該保留，哪些必須清除。在蛋白質(zhì)被送入蛋白酶體之前，首先必須給它貼上一種叫做“泛素”的分子標簽。泛素是一種小蛋白，實際上起到了“給垃圾貼標簽”的作用。當足夠多的泛素分子連接在一起形成多聚泛素鏈時，傳遞的信息就變得明白無誤了：銷毀這個蛋白質(zhì)。

要給蛋白質(zhì)貼上這種“泛素標簽”，需要一系列復雜的酶協(xié)同接力完成。其中一類酶叫做E1酶，負責激活泛素；另一類叫做E2酶，負責運輸泛素；最后，也是選擇性最強的酶是E3連接酶，它們就像分子之間的“中介”，能夠識別特定的目標蛋白、為其貼上“判令處決”的泛素標簽。

這一系統(tǒng)的精準性，是維系生命本身的生死存亡的核心。細胞要依靠它來調(diào)節(jié)從分裂、生長到應(yīng)激反應(yīng)和DNA修復的各個過程。它還肩負著嚴格的質(zhì)量控制工作——科學家目前估計，多達30%的新合成蛋白質(zhì)在生成后不久就被分解了，因為它們沒能達到細胞的“質(zhì)量控制”標準。

到了20世紀90年代末和21世紀初，泛素-蛋白酶體通路已成為現(xiàn)代生物學中最重要的發(fā)現(xiàn)之一。2004年，阿龍·切哈諾沃（Aaron Ciechanover）、阿夫拉姆·赫什科（Avram Hershko）和歐文·羅斯（Irwin Rose）因揭示了這一系統(tǒng)背后的化學原理而榮獲諾貝爾化學獎——細胞如何通過泛素標記不需要的蛋白質(zhì)，并將其引導至蛋白酶體進行快速降解，從而調(diào)控蛋白質(zhì)的存在。

諾貝爾獎委員會在宣布該獎項的公告中，暗示了這一發(fā)現(xiàn)蘊含的深遠治療潛力。“泛素系統(tǒng)已成為針對多種疾病開發(fā)治療藥物的一個有吸引力的靶點，”公告中寫道。公告還提到，或許有朝一日，科學家們不僅能學會阻止重要蛋白質(zhì)的降解，還能學會有意觸發(fā)有害蛋白質(zhì)的銷毀。

對于克魯斯和德沙耶而言，他們正朝著這個“未來”前進——它早在幾年前便已初具雛形。

轉(zhuǎn)折點

兩位科學家設(shè)想的理念，依賴于能否“劫持”細胞自身的一種E3連接酶——它就像分子的“把關(guān)人”，負責決定哪些蛋白質(zhì)能存活、哪些要被送去銷毀。德沙耶實驗室發(fā)現(xiàn)的SCF復合體結(jié)構(gòu)龐大而復雜，但它恰恰提供了兩位科學家需要的東西：一種能募集泛素機制、并作用于他們所選的目標蛋白上的方法。

2001年，這一設(shè)想首次得到了真正的驗證，兩個團隊在《美國國家科學院院刊》（PNAS）上發(fā)表了一篇論文。他們描述的一種蛋白降解靶向嵌合體（Proteolysis Targeting Chimera）分子大膽而又創(chuàng)新，其結(jié)構(gòu)很簡潔——這是一種充當“轉(zhuǎn)接頭”的雙功能分子，一端包含一段能夠募集SCF復合體的短磷酸多肽，另一端則攜帶卵假散囊菌素（ovalicin，一種已知能與MetAP-2蛋白結(jié)合的天然產(chǎn)物化合物）。

這項實驗之所以格外引人注目，是因為人們此前知道MetAP-2蛋白不會在自然條件下被SCF復合體泛素化。如果這個蛋白降解靶向嵌合體分子能促成這種泛素化作用發(fā)生，就能驗證這種全新的藥物作用機制。

事實也確實如此。只有在這一蛋白降解靶向嵌合體分子存在的情況下，MetAP-2才會被泛素化，隨后被降解。論文結(jié)尾做了一個預測：“未來，這種方法可能有助于讓蛋白質(zhì)在一定條件下被滅活，以及靶向致病蛋白以將其銷毀。”

兩年后，克魯斯和德沙耶創(chuàng)立了一家名為Proteolix的公司，希望將這一概念轉(zhuǎn)化為藥物。但當時的時機并不友好，生物技術(shù)泡沫的破滅，讓投資者對雄心勃勃的平臺技術(shù)持謹慎態(tài)度，對非常規(guī)的藥物模式也持懷疑態(tài)度。風險投資人想要的是那些路徑清晰明確、能快速進入臨床的成熟小分子，而不是聽起來不像是實用療法的降解劑。

“一位風險投資人把我們拉到一邊說，‘聽我一句勸，我們很欣賞你們，但我們對用多肽做的降解劑那套東西不感興趣，’”克魯斯回憶道，“‘你們還有別的想法嗎？’”

巧的是，他們還真有。

當時，克魯斯的實驗室也在研究環(huán)氧霉素（epoxomicin），這是一種從土壤放線菌中分離出的天然產(chǎn)物，它能選擇性地抑制蛋白酶體本身。與試圖重塑降解機制的蛋白降解靶向嵌合體不同，環(huán)氧霉素能直接“關(guān)停”整個降解系統(tǒng)。公司隨即調(diào)整了研究方向。這一決定最終促成了卡非佐米（carfilzomib）的開發(fā)，它是環(huán)氧霉素的衍生物，于2012年獲FDA批準用于治療多發(fā)性骨髓瘤。通過抑制蛋白酶體，這款藥物能讓惡性腫瘤細胞積累廢棄蛋白質(zhì)達到毒性水平，最終導致這些細胞滅亡。

這個“有心栽花、無心插柳”的轉(zhuǎn)折，也讓人感嘆不已——曾經(jīng)設(shè)想利用細胞“廢物處理系統(tǒng)”來銷毀有害蛋白的科學家，卻率先通過“關(guān)停這個系統(tǒng)”獲得突破。

蛋白降解靶向嵌合體

“從實驗室里的構(gòu)想到新藥最終獲批，跑完這一整個流程后，我對創(chuàng)建公司到底需要什么有了更深刻的理解，”克魯斯后來反思道。

卡非佐米的成功，正是對這一經(jīng)驗的見證。但即便Proteolix公司正朝著上市抗癌療法邁進，克魯斯也從未放棄最初與德沙耶在對談中萌生的蛋白降解靶向嵌合體的概念。縈繞在他心頭的，還有阻攔它真正能作為藥物在人體中使用的重要障礙——多肽。這一點，也是當初投資者幾乎在看到方案那一瞬間就提出來的顧慮。

他們早期設(shè)想的蛋白降解靶向嵌合體依賴于多肽片段來募集E3連接酶，但在口服可行性方面，這帶來了一個嚴峻的問題。基于多肽片段構(gòu)建的蛋白降解靶向嵌合體結(jié)構(gòu)復雜，分子量大，在口服吸收和穿越細胞膜方面面臨著重大挑戰(zhàn)。這些阻礙導致研發(fā)進程一度停滯不前。

克魯斯意識到，要讓蛋白降解靶向嵌合體成為真正的藥物，必須把多肽的部件整塊放棄掉。

2008年左右，他的團隊開始了艱苦的“回爐重造”，從頭開始設(shè)計整個分子構(gòu)架。首先，他們需要找到一種小分子，它能夠以足夠的特異性和親和力結(jié)合E3連接酶、以取代多肽作為募集泛素的部件，然后將其整合到一個能在活細胞內(nèi)發(fā)揮作用的雙功能降解劑中。

“我們花了4年時間克服化學、結(jié)構(gòu)生物學以及各種必要的分析檢測方法的挑戰(zhàn)，最終找到了一種能夠結(jié)合E3連接酶的小分子配體，”克魯斯回憶道，“目標是制造一種全部由小分子構(gòu)成的蛋白降解靶向嵌合體。”

2015年，突破性進展來了。在一篇具有里程碑意義的論文中，克魯斯的團隊報告了新一代、整體由小分子配體構(gòu)建的蛋白降解靶向嵌合體。通過采用一種結(jié)構(gòu)緊湊的化學結(jié)合劑取代多肽的部件，他們創(chuàng)造出的降解劑分子比早期原型分子效力更強、選擇性更高，也更具成藥性。在小鼠研究中，這些分子在多種組織（包括實體瘤）中都實現(xiàn)了疾病相關(guān)蛋白的靶向降解，表明這種方法最終可能具有治療實用性。

“它或許不是最漂亮的分子，”克魯斯后來說，“但至少是我們能實實在在地作為藥物來開發(fā)的分子了。”

圖片來源：123RF

隨著這一突破，該領(lǐng)域仿佛幾乎是在一夜之間發(fā)生了轉(zhuǎn)變。曾經(jīng)看似古怪的化學生物學“旁門左道”，突然間似乎成為一種全新的藥物發(fā)現(xiàn)范式的開端。

“當我們有了小分子替代物的那一刻，”克魯斯回憶道，“我才意識到，這可能會從根本上改變藥物開發(fā)的方式。”

應(yīng)用

2015年的這篇論文不僅引起了關(guān)注，更動搖了科學家們關(guān)于“藥物應(yīng)該是什么樣”的長期假設(shè)。業(yè)內(nèi)人士的反應(yīng)，在感興趣與懷疑之間搖擺不定。

一些科學家懷疑，比傳統(tǒng)小分子大得多的蛋白降解靶向嵌合體分子是否能有效地進入細胞。

另一些科學家的擔心則相反——降解劑的作用可能過于強大了。如果蛋白降解靶向嵌合體持續(xù)募集E3連接酶來銷毀目標蛋白，會不會干擾細胞自身精密的蛋白質(zhì)調(diào)控機制？會不會“壟斷”泛素系統(tǒng)、阻止E3連接酶發(fā)揮其天然功能，從而導致危險的副作用？

隨著時間的推移，許多這類擔憂都通過實驗被證明是可控的。研究人員證實，盡管蛋白降解靶向嵌合體背離了諸多指導藥物化學研究數(shù)十年的傳統(tǒng)規(guī)則，但它確實可以實現(xiàn)口服生物利用度并在體內(nèi)產(chǎn)生顯著活性。隨著該領(lǐng)域發(fā)展出新的藥理學概念——比如DC50（即降解一半靶蛋白所需的分子濃度，是衡量蛋白降解劑效果的指標）和Dmax（分子可達到的最大降解程度）等指標——關(guān)于效力和選擇性的問題也變得更容易處理。這些指標部分由克魯斯的實驗室率先提出，在它們的幫助下，研究人員不再把降解劑當作抑制劑，而是把它視為一種迥然不同的藥理學類別。

然而，更重要的問題并非停留于技術(shù)層面：為什么一開始需要探索蛋白質(zhì)降解？既然抑制劑已經(jīng)被證明有效，為什么還要發(fā)明一種全新的分子模式？

在克魯斯看來，答案在于“抑制”本身是有局限性的。傳統(tǒng)的小分子藥物，一般通過占據(jù)蛋白質(zhì)上的功能性結(jié)合位點并抑制其活性來發(fā)揮作用。但許多致病蛋白上幾乎不存在這樣的結(jié)合位點。到21世紀初，科學家已經(jīng)繪制出了大部分的人類遺傳圖譜，并鑒定出大量潛在的疾病相關(guān)蛋白。然而，只有大約25%的蛋白質(zhì)組似乎可以通過傳統(tǒng)方法開發(fā)出的藥物進行靶向干預，其余的蛋白質(zhì)組常被貼上“不可成藥”的標簽。

克魯斯越來越覺得這個術(shù)語具有誤導性。“這些蛋白質(zhì)不一定是不可成藥的，它們只是還沒遇到能影響它們的藥物。”

蛋白質(zhì)降解提供了一種根本不同的方法。與一般需要精準結(jié)合功能位點才能“壓制”蛋白質(zhì)活性的傳統(tǒng)抑制劑不同，蛋白降解靶向嵌合體僅通過表面的相互作用即可發(fā)揮其功能，從而大大擴展了可能成為治療靶點的蛋白質(zhì)范圍。

“我不想與抑制劑競爭，而是想與它們互補，”他補充道。

在其他一些情況下，單純的抑制作用是暫時性的、也是脆弱的。比如，癌細胞面對抑制作用，往往會產(chǎn)生更多靶蛋白或激活其他代償性反饋回路，最終恢復致病通路。

而蛋白降解靶向嵌合體無需反復阻斷致病蛋白活性，而是可以直接清除致病蛋白本身。它的藥理學變成了基于“事件”的藥理學，而不是基于“占位”的藥理學：一旦“降解事件”發(fā)生，藥物分子就完成任務(wù)了，不再需要持續(xù)“占住”結(jié)合位點、與致病蛋白保持結(jié)合才能發(fā)揮其作用。

這些區(qū)別成為了整個領(lǐng)域的認知基礎(chǔ)之一。

業(yè)界開始以驚人的速度做出響應(yīng)。在接下來的幾年里，之前那篇2015年發(fā)表于《自然-化學生物學》（Nature Chemical Biology）的論文引用量急劇上升，助推著靶向蛋白降解從“學術(shù)性好奇的產(chǎn)物”轉(zhuǎn)變?yōu)樗幬锇l(fā)現(xiàn)中備受關(guān)注的領(lǐng)域之一。圍繞這一概念，初創(chuàng)公司如雨后春筍般涌現(xiàn)，其中就包括克魯斯于2013年率先創(chuàng)立的Arvinas公司，旨在將蛋白降解靶向嵌合體療法推向臨床。

十年后，該領(lǐng)域迎來了里程碑式的進展。2026年5月，Arvinas公司與輝瑞（Pfizer）公司共同宣布，FDA已批準vepdegestrant（商品名：Veppanu）用于治療特定乳腺癌患者。這一決定標志著史上首個蛋白降解靶向嵌合體療法的獲批。

圖片來源：123RF

對克魯斯而言，首款蛋白降解靶向嵌合體療法的獲批意義重大。然而真正具有決定意義的時刻，并不是首批臨床結(jié)果出爐的那一刻，也不是收到新藥獲批消息的那一刻。到那時，他已經(jīng)對自己的科學理念深信不疑了。更深刻的意義感，來自于一個平靜得甚至有些近乎尋常的瞬間：那是他第一次親眼見到準備用于后期開發(fā)的蛋白降解靶向嵌合體藥物的實物。

“還記得那天，我第一次親眼看到了那袋5公斤重的、即將用于后期開發(fā)的蛋白降解靶向嵌合體藥物粉末，”他回憶道，“那一刻真的觸動了我。”

未來

當被問及“蛋白降解靶向嵌合體之后的下一步設(shè)想”，克魯斯沉吟片刻便給出了答案。他相信，未來在于對“蛋白質(zhì)-蛋白質(zhì)”的相互作用進行更廣泛的重新構(gòu)想——這種復雜的分子關(guān)系支配著生物學的諸多方面，但遺憾的是，長期以來，藥物發(fā)現(xiàn)卻對此難以觸及。

克魯斯相信，誘導接近技術(shù)提供了一種繞過這一限制的通路。

目前，他關(guān)注的眾多概念之一是調(diào)節(jié)誘導接近靶向嵌合體（Regulated Induced Proximity Targeting Chimera），這種新分子由他聯(lián)合創(chuàng)立的第三家公司Halda Therapeutics開發(fā)，該公司于2025年被強生（Johnson & Johnson）收購。與蛋白降解靶向嵌合體通過募集E3連接酶來消除靶蛋白不同，調(diào)節(jié)誘導接近靶向嵌合體的目的是在細胞內(nèi)強制“綁定”兩種蛋白質(zhì)、讓它們形成新的“合作關(guān)系”。這種分子能同時結(jié)合腫瘤特異性蛋白和另一種對細胞生存的必需蛋白、形成一種穩(wěn)定的非天然三元復合物，從而破壞必需蛋白的功能并選擇性地殺死癌細胞。

在克魯斯看來，這種方法預示著，未來藥物的作用方式將不再是全身性、無差別地發(fā)揮作用，而是只在疾病發(fā)生的特定組織中精準生效。

“我不認為20年后傳統(tǒng)抑制劑還是藥物開發(fā)的主流，”他說，“未來在很大程度上將基于誘導接近機制發(fā)展。”

在他看來，其中的邏輯簡明而清晰——傳統(tǒng)抑制劑會抑制體內(nèi)各個部位靶蛋白的活性，這往往對健康組織造成毒性。但調(diào)節(jié)誘導接近靶向嵌合體則不同，它理論上可能只在有組織特異性“伙伴蛋白”存在的部位發(fā)揮作用。例如，一種圍繞骨骼肌特異性蛋白設(shè)計的調(diào)節(jié)誘導接近靶向嵌合體，可能只抑制骨骼肌中的某種酶，同時幾乎不影響心肌。

這一設(shè)想依然壯志滿懷，而生物很少會毫無抵抗地做出“讓步”。特別是癌細胞，它們在治療壓力下進化出應(yīng)對機制的能力是出了名的。然而克魯斯懷疑，誘導接近療法的耐藥機制可能與傳統(tǒng)抑制劑有著根本的不同。

他認為原因之一在于蛋白質(zhì)-蛋白質(zhì)相互作用本身的性質(zhì)。過去幾十年，科學家一直試圖用小分子破壞蛋白質(zhì)-蛋白質(zhì)相互作用，卻一次又一次發(fā)現(xiàn)，要瓦解這些結(jié)合面是如此困難。與酶緊湊的結(jié)合位點不同，蛋白質(zhì)-蛋白質(zhì)的結(jié)合通常會跨越廣闊而靈活的界面。如果一種藥物是通過“建立或穩(wěn)定一個大的蛋白質(zhì)-蛋白質(zhì)結(jié)合面”發(fā)揮作用，即便蛋白發(fā)生了單點突變，它或許只會改變廣闊接觸面上的其中一個接觸點，但整個大界面的相互作用依然可以維持（藥物不一定因此失效）。

夢想

歷經(jīng)20多年沉浮，當初那場由“兩張冷清的海報”引發(fā)的對談，如今已傳為一段佳話。克魯斯參與創(chuàng)立的領(lǐng)域正不斷發(fā)展壯大，比起初那個雄心勃勃的設(shè)想走得更深、更遠。一開始關(guān)于“勸細胞摧毀某個特定的問題蛋白”的嘗試，而今已演變成一個更宏大的理念：“誘導接近機制”本身，可能成為未來醫(yī)學領(lǐng)域強有力的思維框架之一。

更令克魯斯興奮的是，他看到了為這樣的未來構(gòu)建分子圖譜的可能性：把能與人類蛋白質(zhì)組中每個蛋白質(zhì)結(jié)合的配體，都編進一本“綜合目錄”，即覆蓋幾乎整個蛋白質(zhì)組的配體庫。如果存在這樣一個工具包，研究人員理論上可以用幾乎模塊化的方式“組裝”誘導接近療法藥物分子：針對疾病相關(guān)靶點選擇一種配體，再針對組織特異性蛋白選擇另一種配體，然后將它們組合成一種全新的藥物類別。

圖片來源：123RF

“我的夢想，”克魯斯說，“是擁有整個蛋白質(zhì)組的目錄以及每個蛋白質(zhì)對應(yīng)的配體。這樣每當我們有了一個想法，就可以直接從‘貨架’上挑出現(xiàn)成的部件，來構(gòu)建我們需要的分子。”

The Molecules of His Dreams

How Proteylysis Targeting Chimeras are Rewriting the Rules of Small Molecules

Many years later, staring at five kilograms of pale drug powder sealed inside a plastic bag, Craig Crews remembered that afternoon in the late 1990s, when almost nobody stopped to see his poster.

He was not entirely alone. The posters had been arranged alphabetically by last name, and beside his stood another young scientist’s work, belonging to a researcher named Raymond Deshaies. As the hours passed and few attendees stopped to ask questions, the two men began talking to each other instead.

Craig Crews was then a junior faculty member at Yale University, thinking obsessively about an unusual chemical idea: heterobifunctional molecules capable of tethering two proteins together inside a cell, forcing them into close enough proximity to interact. Deshaies, a yeast geneticist at Caltech, had spent years studying the machinery that governs the cell cycle. In 1997, his lab identified a protein complex known as SCF, part of the elaborate proteasome pathway — the cell’s internal disposal system, responsible for recognizing and dismantling unwanted proteins.

What if, the two scientists began to wonder, a molecule could bring these worlds together?What if a drug could physically drag a disease-causing protein to the cell’s own degradation machinery and mark it for destruction?Modern medicines, after all, were largely built on inhibition: blocking a protein’s activity, shutting something down, suppressing a signal. But this idea was different. It imagined a drug that could make a problematic protein disappear altogether.

“After a few beers, we started talking about using heterobifunctional molecules to hijack the protein degradation system,” Crews later recalled. “That was really the genesis moment.”

More than two decades later, the idea born from that late-night conversation would culminate in the first FDA-approved Proteylysis Targeting Chimera therapy, opening the door to an entirely new class of medicines: drugs designed not simply to inhibit proteins, but to erase them from the cell entirely.

Image source：123RF

The Nobel Prize

The idea that fascinated Crews and Deshaies rested on one of the cell’s most elegant housekeeping systems. Inside a human cell are tens of thousands or even millions of proteasomes, barrel-shaped molecular structures that function like highly sophisticated disposal units. Their job is relentless and essential: to identify unwanted, damaged, or surplus proteins and break them down into recyclable fragments.

But the system is not indiscriminate. A cell cannot afford to destroy proteins carelessly; survival depends on knowing precisely what should remain and what must go. Before a protein can be fed into the proteasome, it first has to be marked with a molecular tag known as ubiquitin, a small protein that acts, in effect, as a disposal label. When enough ubiquitin molecules are linked together into a polyubiquitin chain, the message becomes unmistakable: destroy this protein.

Attaching that label requires an intricate relay of enzymes. One class, known as E1 enzymes, activates ubiquitin. Another, E2 enzymes, carries it. The final and most selective actors are the E3 ligases, molecular matchmakers that recognize specific target proteins and attach the ubiquitin label that condemns them to destruction.

The precision of this system is central to life itself. Cells rely on it to regulate everything from division and growth to stress responses and DNA repair. It also serves as a stringent quality-control mechanism: scientists now estimate that as many as thirty percent of newly synthesized proteins are dismantled shortly after being made because they fail to meet the cell’s protein quality standards.

By the late 1990s and early 2000s, the ubiquitin-proteasome pathway had emerged as one of the most important discoveries in modern biology.In 2004, Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry for uncovering the chemical principles behind this system — how cells regulate the presence of proteins by labeling unwanted ones with ubiquitin and directing them to the proteasome for rapid degradation.

The Nobel committee, in its announcement, hinted at the profound therapeutic possibilities embedded within the discovery. “The ubiquitin system has become an interesting target for the development of drugs against various diseases,” the statement read.Scientists, it suggested, might one day learn not only to prevent the degradation of important proteins, but also to deliberately trigger the destruction of harmful ones.

For Crews and Deshaies, that future had already begun to take shape years earlier.

The Pivot

The concept the duo envisioned depended on hijacking one of the cell’s own E3 ligases — the molecular gatekeepers responsible for deciding which proteins live and which are sent to destruction. The SCF complex identified by Deshaies’s laboratory was enormous and intricate, but it offered precisely what the two scientists needed: a way to recruit the ubiquitin machinery to a target protein of their choosing.

The first real demonstration arrived in 2001, when the two groups published a paper in theProceedings of the National Academy of Sciences.The molecule they described — Protac-1 — was audacious in its simplicity, a bifunctional molecule acting as an adapter: one end contained a short phosphopeptide capable of recruiting the SCF complex. The other end carried ovalicin, a natural-product compound known to bind a protein called MetAP-2.

What made the experiment especially striking was that MetAP-2 was not known to be naturally ubiquitinated by the SCF complex. If the system worked, the Protac-1 molecule itself would be responsible for forcing the interaction, effectively creating an entirely new biological relationship inside the cell.

And that was precisely what happened. MetAP-2 became ubiquitinated, then degraded, only in the presence of Protac-1. The paper ended with a prediction that, in retrospect, now reads almost understated: “In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.”

Two years later, Crews and Deshaies founded a company called Proteolix, hoping to transform the concept into medicines. But timing proved unforgiving. The collapse of the genomic bubble had left investors wary of ambitious platform technologies and skeptical of unconventional drug modalities. Venture capitalists wanted familiar small molecules with a clear and immediate path to the clinic, not peptide-based degraders that sounded more like speculative biology than practical therapeutics.

“One VC pulled us aside and said, ‘Listen, we like you guys, but we’re not interested in the peptide degradation stuff,’” Crews recalled. “‘Do you have something else?’”

As it happened, they did.

At the time, Crews’s laboratory had also been studying epoxomicin, a natural product isolated from soil-dwelling Actinomycetes that selectively inhibited the proteasome itself. Unlike Proteolysis Targeting Chimeras, which attempted to redirect the degradation machinery, epoxomicin simply shut the system down. The company pivoted. That decision eventually led to the development of carfilzomib, a derivative of epoxomicin approved by the FDA in 2012 for multiple myeloma. By blocking the proteasome, the drug causes malignant cells to accumulate toxic levels of protein waste, ultimately driving them toward death.

The irony was difficult to miss. The scientists who had once imagined harnessing the cell’s disposal system to destroy harmful proteins first found regulatory breakthrough by disabling that very system altogether.

The Proteolysis Targeting Chimeras

“Having gone through the entire process from an idea in the lab to an approved medicine, I had a much better sense of what it actually takes to build a company,” Crews later reflected.

The success of carfilzomib validated that lesson. But even as Proteolix advanced toward a marketed cancer therapy, Crews never abandoned the original Proteolysis Targeting Chimera concept that had first emerged from those conversations with Deshaies years earlier. What lingered in his mind, too, were the challenges he would face to turn this concept into real medicine for patients. One of the challenges was the peptide, which was also a concern that investors had raised almost immediately.

Early Proteolysis Targeting Chimera molecules depended on peptide fragments to recruit E3 ligases, and that presented a serious problem for oral delivery. Due to using peptide as a component, the bulky bifunctional degrader has high molecular weight and a complex structure. Overcoming low oral bioavailability and permeability of cell membrane became a serious challenge which stalled the research progress.

For Proteolysis Targeting Chimeras to become real medicines, Crews realized, the field would have to abandon the peptide altogether.

Around 2008, his group began the painstaking work of redesigning the entire concept from the ground up. First, they needed to discover a small molecule capable of binding an E3 ligase with enough specificity and affinity to replace the peptide recruiter and then integrate it into a bifunctional degrader that could function inside living cells.

“For four years, we worked on the chemistry, the structural biology, and all the assays necessary to come up with a small molecule ligand that could bind an E3 ligase,” Crews recalled. “The goal was to make an all-small-molecule Proteolysis Targeting Chimera.”

The breakthrough arrived in 2015. In a landmark paper, Crews’s team reported a new generation of such molecules built entirely from small-molecule ligands.By replacing the peptide recruiter with a compact chemical binder, they created degraders that were dramatically more potent, more selective, and far more drug-like than the earlier prototypes. In mouse studies, the molecules achieved targeted degradation of disease-related proteins across multiple tissues, including solid tumors — an important demonstration that the approach might finally be therapeutically practical.

Image source：123RF

“It may not have been the prettiest molecule,” Crews said later, “but it was at least something we could realistically work with as a drug.”

And with that, the field seemed to shift almost overnight. What had once looked like an eccentric chemical biology trick suddenly appeared to be the beginning of an entirely new paradigm in drug discovery.

“Once we had the small-molecule replacement,” Crews recalled, “that was when I realized this could fundamentally change how drugs are developed.”

The Adoption

The 2015 paper did not merely attract attention; it unsettled long-standing assumptions about what a drug could be. Within the pharmaceutical industry, reactions oscillated between fascination and skepticism.

Some scientists doubted whether Proteolysis Targeting Chimera molecules, substantially larger than conventional small molecules, could effectively enter cells at all. Others worried about the opposite problem: that the degraders might work too well. If a Proteolysis Targeting Chimera continuously recruited E3 ligases to destroy target proteins, could it interfere with the cell’s own delicate protein-regulation machinery? Might it monopolize the ubiquitin system and prevent E3 ligases from carrying out their natural functions, leading to dangerous side effects?

Over time, many of those concerns proved experimentally manageable.Researchers demonstrated that these molecules could indeed achieve oral bioavailability and meaningful activity in vivo, despite violating many of the conventional rules that had guided medicinal chemistry for decades.Questions surrounding potency and selectivity also became more tractable as the field developed new pharmacological concepts, including measures such as DC50, the concentration required to degrade half of a target protein population, and Dmax, the maximum extent of degradation achievable by a molecule. These metrics, pioneered in part by Crews’s laboratory, helped researchers think about degraders not as inhibitors, but as an entirely different pharmacological class.

Yet the important question was more than technical: why was protein degradation needed in the first place? Why invent an entirely new modality when inhibitors already worked?

For Crews, the answer lay in the limits of inhibition itself. Traditional small-molecule drugs generally work by occupying a functional pocket on a protein and suppressing its activity. But many disease-causing proteins lack such pockets altogether. By the early 2000s, scientists had already mapped much of the human genome and identified vast numbers of potential disease-related proteins. Yet only around 25% of the proteome appeared accessible to conventional drug discovery approaches. The rest were frequently labeled “undruggable.”

Crews increasingly came to see that term as misleading. “These proteins weren’t necessarily undruggable, they were undrugged.”

Protein degradation offered a fundamentally different approach. Unlike conventional inhibitors, which generally require a precise binding pocket to shut down a protein’s activity, Proteolysis Targeting Chimeras can act through surface interactions alone, dramatically expanding the range of proteins that may be therapeutically targeted.

“I didn’t want to compete with inhibitors. I wanted to complement them,” He added.

In still other cases, inhibition alone is temporary and fragile. Cancer cells, for example, often respond to inhibition by producing more of the target protein or activating compensatory feedback loops that eventually restore the disease pathway.

Rather than repeatedly blocking a protein’s activity, a Proteolysis Targeting Chimera could eliminate the protein itself. The pharmacology became event-driven rather than occupancy-driven: once degradation occurred, the molecule no longer needed to remain continuously bound to exert its effect.

Those distinctions became one of the intellectual foundations of the entire field.

The industry began to respond with remarkable speed. Citations of the 2015 Nature Chemical Biology paper rose sharply over the following years, helping transform targeted protein degradation from an academic curiosity into one of the most closely watched areas in drug discovery. Startups formed rapidly around the concept, beginning with Arvinas, the company Crews had founded in 2013 to advance Proteolysis Targeting Chimera therapeutics into the clinic.

A decade later, the field reached the milestone.In May 2026, Arvinas and Pfizer announced that the FDA had approved vepdegestrant, marketed as Veppanu, for certain patients with breast cancer. The decision marked the first approval of a Proteolysis Targeting Chimera therapy in history.

Image source：123RF

To Crews, the approval of the first Proteolysis Targeting Chimera therapy matters. However, the defining moment did not come from the first clinical data or a press release announcing the approval. By then, he already believed in the science.The deeper realization arrived in a far quieter, almost strangely ordinary moment: seeing the physical material of a Proteolysis Targeting Chimera drug prepared for human testing for the very first time.

“I remember seeing the five kilos of the drug that was going to go into humans,” he recalled. “That was the moment when it really hit me.”

The Future

When asked what comes next after Proteolysis Targeting Chimeras, Crews did not hesitate for long. The future, he believes, lies in a broader reimagining of protein-protein interactions (PPIs), the intricate molecular relationships that govern much of biology and have historically remained frustratingly inaccessible to drug discovery.

Induced proximity technologies, Crews believes, offer a way around that limitation.

Among the concepts that now occupy much of his attention is a modality called Regulated Induced Proximity Targeting Chimera, developed through Halda Therapeutics, the third company he co-founded, which was acquired by Johnson & Johnson in 2025. Whereas Proteolysis Targeting Chimeras recruit an E3 ligase to eliminate a target protein, Regulated Induced Proximity Targeting Chimeras are designed to force entirely new protein partnerships inside a cell. The molecule simultaneously binds a tumor-specific protein and a second protein essential for survival, stabilizing an unnatural ternary complex that disrupts the essential protein’s function and selectively kills the cancer cell.

To Crews, the approach suggests a future in which drugs no longer act systemically and indiscriminately, but only within the precise tissues where disease occurs.

“I don’t believe that twenty years from now we’ll still mainly be making traditional inhibitors,” he said. “Everything could become proximity-driven.”

The logic, in his view, is straightforward. A conventional inhibitor suppresses its target wherever the protein exists in the body, often creating toxicities in healthy tissues.But an induced-proximity molecule could, in principle, work only where a tissue-specific partner protein is present.A Regulated Induced Proximity Targeting Chimera designed around a skeletal-muscle-specific protein, for example, might inhibit an enzyme in skeletal muscle while sparing cardiac muscle entirely.

The vision remains ambitious, and biology rarely yields without resistance. Cancer cells, in particular, have a notorious ability to evolve around therapeutic pressure. Yet Crews suspects that resistance mechanisms for induced-proximity drugs may differ fundamentally from those seen with traditional inhibitors.

One reason, he argues, lies in the very nature of protein-protein interactions themselves. Scientists have spent decades trying to disrupt PPIs with small molecules and have repeatedly discovered how difficult those interfaces are to break apart. Unlike the compact binding pockets of enzymes, protein-protein interfaces often span broad and flexible surfaces. If a drug functions by creating or stabilizing a large protein-protein interface, a single mutation may alter one contact point without necessarily destabilizing the interaction entirely.

The Dream

More than twenty-five years after a conversation beside two largely ignored posters, the field Crews helped create continues to expand beyond its original ambitions. What began as an attempt to persuade the cell to destroy a single problematic protein has evolved into a broader idea: that proximity itself may become one of the most powerful organizing principles in the future of medicine.

What excites Crews most is the possibility of building a molecular atlas for this future: a comprehensive catalog of ligands capable of binding proteins across the human proteome.If such a toolkit existed, researchers could theoretically assemble induced-proximity therapeutics almost modularly: selecting one ligand for a disease-related target, another for a tissue-specific protein, and combining them into entirely new classes of medicines.

Image source：123RF

“My dream,” Crews said, “is to have a catalog of the entire proteome and corresponding ligands for each protein, so when we have an idea, we can essentially pull components off the shelf and build the molecule we need.”

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