Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.
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XL01126的发现：一种有效，快速，合作，选择性，口服生物利用，以及富含亮氨酸的重复激酶2的血脑屏障渗透剂protac Degrader。
DOI：
10.1021/jacs.2c05499
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发表时间：
2022-09-21
影响因子：
15
通讯作者：
Ciulli, Alessio
中科院分区：
文献类型：
--
作者：
Liu, Xingui;Kalogeropulou, Alexia F.;Domingos, Sofia;Makukhin, Nikolai;Nirujogi, Raja S.;Singh, Francois;Shpiro, Natalia;Saalfrank, Anton;Sammler, Esther;Ganley, Ian G.;Moreira, Rui;Alessi, Dario R.;Ciulli, Alessio
富含亮氨酸重复激酶 2 (LRRK2) 是帕金森病最有希望的靶标之一。 LRRK2 靶向策略主要集中于 1 型激酶抑制剂，但其具有局限性，因为受抑制的蛋白质会干扰自然机制，从而可能导致不良副作用。在此，我们报告了 LRRK2 蛋白水解靶向嵌合体 (PROTAC) 的开发，最终发现了降解剂 XL01126，作为替代 LRRK2 靶向策略。基于 E3 连接酶 von Hippel-Lindau (VHL)、Cereblon (CRBN) 和细胞凋亡抑制剂 (cIAP) 配体的 PROTAC 的初步设计和筛选确定了含有硫醚缀合的 VHL 配体 VH101 的最佳降解剂。第二轮药物化学探索使 XL01126 成为多种细胞系中 LRRK2 的快速有效降解剂，其 DC50 值在 15-72 nM 范围内，Dmax 值在 82% 到 90% 范围内，降解半衰期从 0.6 到 2.4 小时。 XL01126 表现出高细胞渗透性，并与 VHL 和 LRRK2 (α = 5.7) 形成正协同三元复合物，弥补了与 VHL 和 LRRK2 二元结合亲和力的大幅损失，强调了其在细胞中的强大降解性能。值得注意的是，XL01126 具有口服生物利用度（F = 15%），并且在小鼠口服或肠胃外给药后可以穿透血脑屏障。总而言之，这些实验使 XL01126 成为一种合适的降解剂探针，用于研究 LRRK2 体外和体内的非催化和支架功能，并为未来的药物开发提供一个有吸引力的起点。
Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the development of LRRK2 proteolysis targeting chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2-targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), and cellular inhibitor of apoptosis (cIAP) identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15–72 nM, Dmax values ranging from 82 to 90%, and degradation half-lives spanning from 0.6 to 2.4 h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α = 5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F = 15%) and can penetrate the blood–brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study the noncatalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.
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影响因子：
7.3
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
通讯作者：
Ciulli A
影响因子：
14.8
作者：
Adhikari B;Bozilovic J;Diebold M;Schwarz JD;Hofstetter J;Schröder M;Wanior M;Narain A;Vogt M;Dudvarski Stankovic N;Baluapuri A;Schönemann L;Eing L;Bhandare P;Kuster B;Schlosser A;Heinzlmeir S;Sotriffer C;Knapp S;Wolf E
通讯作者：
Wolf E
脑渗透 LRRK2 抑制剂。
影响因子：
4.2
作者：
Choi, Hwan Geun;Zhang, Jinwei;Deng, Xianming;Hatcher, John M.;Patricelli, Matthew P.;Zhao, Zheng;Alessi, Dario R.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
7.3
作者：
Churcher, Ian
通讯作者：
Churcher, Ian
影响因子：
64.8
作者：
Deniston CK;Salogiannis J;Mathea S;Snead DM;Lahiri I;Matyszewski M;Donosa O;Watanabe R;Böhning J;Shiau AK;Knapp S;Villa E;Reck-Peterson SL;Leschziner AE
通讯作者：
Leschziner AE