撰文丨王聪

编辑丨王多鱼

排版丨水成文

近日。临床阶段生成式人工智能

（AI）驱动的生物科技公司

英矽智能

（Insilico Medicine）宣布，发现了一款高选择性的口服小分子抑制剂

ISM9682

，以靶向有丝分裂驱动蛋白 

KIF18A，

有望用于

治疗TP53突变的晚期实体瘤，尤其是高级别浆液性卵巢癌

（HGSOC）、三阴性乳腺癌

（TNBC）和非小细胞肺癌

（NSCLC）。

该小分子抑制剂使用英矽智能的 Chemistry42 生成式AI平台从头设计，因此与其他正在开发中的 KIF18A 抑制剂不同。

染色体不稳定性

（CIN）

是癌症的特征之一，由有丝分裂过程中染色体分离的持续错误造成。KIF18A是一种沿微管移动的驱动蛋白，在有丝分裂过程中发挥关键作用。研究表明，KIF18A抑制剂能激活有丝分裂检查点，并选择性杀伤染色体不稳定的癌细胞，作为潜在肿瘤治疗策略具有广阔前景。

Alex Zhavoronkov

英矽智能目前正在进行 

ISM9682 治疗晚期实体瘤的 IND 申请

。公司

创始人、董事长兼首席执行官 Alex Zhavoronkov 博士表示，

我们基于公司的 PandaOmics 平台的疾病和靶点相关性分析，得出结论——KIF18A 是晚期肿瘤治疗的有前途的靶点。

我们进一步将分析与广泛的生物研究相结合，并启动了针对 KIF18A 的内部研发计划。在这个计划中，我们使用了公司的 Chemistry 42 生成式 AI 平台的基于结构的分子设计方法来设计靶向 KIF18A 的化合物，设计了一系列具有新颖大环结构的小分子抑制剂，

在合成和测试了大约110个小分子抑制剂后，ISM9682 脱颖而出。

我们期待尽快将该项目推进到临床阶段。

在临床前研究中，ISM9682 在多个

染色体不稳定性

（CIN）癌症细胞系和细胞系衍生的异种移植

（CDX）模型中显示了广泛的抗肿瘤活性，包括

高级别浆液性卵巢癌

（HGSOC）

、三阴性乳腺癌

（TNBC）

和非小细胞肺癌

（NSCLC）

，ISM9682 

表现出良好的口服生物利用度和安全性，与其他已发表的 KIF18A 抑制剂相比，其可在较低的剂量下发挥作用。

据悉，

英矽智能

计划于今年4月5-10日在圣地亚哥举行的美国癌症研究协会

（AACR）年会上展示其 KIF18A 抑制剂项目的数据，还计划向有兴趣合作开发 ISM9682 的公司展示这些数据。

目前开发进度最靠前的 

KIF18A 抑制剂是 

Sovilnesib

（原名AMG650）

，是一种由安进公司

（Amgen）开发的口服小分子 KIF18A 抑制剂，用于治疗晚期实体瘤。去年，Volastra Therapeutics 从安进获得了该抑制剂的除中国以外地区的全球独家授权，预计在今年第一季度启动 1b 期临床试验，旨在评估 Sovilnesib 在不同剂量水平下治疗

高级别浆液性卵巢癌

（HGSOC）的安全性、耐受性、药代动力学和疗效。

Volastra Therapeutics 还在开发另一款口服小分子 KIF18A 抑制剂——VLS-1488，目前正在进行1/2期临床试验的1期部分研究，预计将于今年10月份进行首位患者给药。

此外，还有多家制药公司在开发 

KIF18A 抑制剂，但还都处于临床前阶段。

英矽智能联合首席执行官兼首席科学官任峰博士表示，“靶向 KIF18A 以抑制 CIN 相关癌症是药物发现领域的一种新兴治疗策略，具有广阔的临床前景。很高兴看到我们的团队在 Chemistry42 的启发下发现了一款药效强大、安全性特征良好的新颖分子。随着IND-enabling研究的进展，我们期待适应症拓展研究得出有启发性的结果，并将该项目推进到临床阶段。”

据悉，ISM9682 是

英矽智能自 2021 年以来提名的第 18 个临床前候选药物，目前其候选药物已超过 30 种，其中有 6 种正在进行临床试验，有 2 种处于 2 期临床阶段。

参考资料：

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rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]).my_comment_empty_data{background-color:#111}}body,.wx-root{--weui-BG-6: rgba(0, 0, 0, .05);--weui-ACTIVE-MASK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-REDORANGE: #ff6146;--weui-BG-0: #ededed;--weui-BG-1: #f7f7f7;--weui-BG-2: #fff;--weui-BG-3: #f7f7f7;--weui-BG-4: #4c4c4c;--weui-BG-5: #fff;--weui-FG-0: rgba(0, 0, 0, .9);--weui-FG-HALF: rgba(0, 0, 0, .9);--weui-FG-1: rgba(0, 0, 0, .55);--weui-FG-2: rgba(0, 0, 0, .3);--weui-FG-3: rgba(0, 0, 0, .1);--weui-FG-4: rgba(0, 0, 0, .15);--weui-FG-5: rgba(0, 0, 0, .05);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #fa9d3b;--weui-YELLOW: #ffc300;--weui-GREEN: #91d300;--weui-LIGHTGREEN: #95ec69;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1485ee;--weui-PURPLE: #6467f0;--weui-WHITE: #fff;--weui-LINK: #576b95;--weui-TEXTGREEN: #06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-BG-0: #ededed;--weui-BG-1: #f7f7f7;--weui-BG-2: #fff;--weui-BG-3: #f7f7f7;--weui-BG-4: #4c4c4c;--weui-BG-5: #fff;--weui-FG-0: rgba(0, 0, 0, .9);--weui-FG-HALF: rgba(0, 0, 0, .9);--weui-FG-1: rgba(0, 0, 0, .55);--weui-FG-2: rgba(0, 0, 0, .3);--weui-FG-3: rgba(0, 0, 0, .1);--weui-FG-4: rgba(0, 0, 0, .15);--weui-FG-5: rgba(0, 0, 0, .05);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #fa9d3b;--weui-YELLOW: #ffc300;--weui-GREEN: #91d300;--weui-LIGHTGREEN: #95ec69;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1485ee;--weui-PURPLE: #6467f0;--weui-WHITE: #fff;--weui-LINK: #576b95;--weui-TEXTGREEN: #06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}.wx-root,body{--weui-BTN-ACTIVE-MASK: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BTN-DEFAULT-ACTIVE-BG: #e6e6e6}.wx-root,body{--weui-DIALOG-LINE-COLOR: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BG-COLOR-ACTIVE: #ececec}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-DEFAULT-ACTIVE-BG: rgba(255, 255, 255, .126)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-DIALOG-LINE-COLOR: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-BG: #1E1E1E}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--APPMSGCARD-LINE-BG: rgba(255, 255, 255, .07)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-COLOR-ACTIVE: #373737}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-6: rgba(255, 255, 255, .1);--weui-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-REDORANGE: #ff6146;--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--discussInput-BG: rgba(255, 255, 255, .03)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--nickName-FG: #959595}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-ORANGERED: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}.rich_media_content p{clear:both;min-height:1em}td p{margin:0;padding:0}@media screen and (min-width:1024px){body:not(.pages_skin_pc) :root{--appmsgPageGap: 20px;--appmsgPageBottomGap: 40px}}:root{--articleFontsize: 17px}:root{--sab: env(safe-area-inset-bottom)}:root{--wxBorderAvatarRatio: 3}:root{--discussPageGap: 20px}:root{--immersive-safe-bottom: env(safe-area-inset-bottom)}:root{--appmsgPageGap: 20px;--appmsgPageBottomGap: 40px}

div.autoTypeSetting24psection > p,div.autoTypeSetting24psection > section{margin-bottom: 24px;}