Citation: Shiyang Sun, Ning Yang, Yaqiu Mao, Ting Wei, Pengli Wei, Tingting Yang, Yixin Zhang, Jian Yan, Changkai Jia, Yi Li, Xu Cai, Zhiyuan Zhao, Xuesong Feng, Xiaomei Zhuang, Wenpeng Zhang, Junhai Xiao, Pengyun Li, Zhibing Zheng, Song Li. Rational design of VHL-recruiting KRAS^G12C proteolysis-targeting chimeras based on molecular dynamics simulation[J]. Chinese Chemical Letters, ;2026, 37(2): 110992. doi: 10.1016/j.cclet.2025.110992 shu

Rational design of VHL-recruiting KRAS^G12C proteolysis-targeting chimeras based on molecular dynamics simulation

Shiyang Sun ^{a, b, 1} ,
Ning Yang ^{a, b, 1} ,
Yaqiu Mao ^{a, c} ,
Ting Wei ^{a, b} ,
Pengli Wei ^{a, c} ,
Tingting Yang ^d ,
Yixin Zhang ^b ,
Jian Yan ^{a, b} ,
Changkai Jia ^{a, b} ,
Yi Li ^{a, b} ,
Xu Cai ^{a, b} ,
Zhiyuan Zhao ^{a, b} ,
Xuesong Feng ^c ,
Xiaomei Zhuang ^b ,
Wenpeng Zhang ^{b, *,} ,
Junhai Xiao ^{a, b, *,} ,
Pengyun Li ^{a, b, *,} ,
Zhibing Zheng ^{a, b, *,} ,
Song Li ^{a, b}

a.
National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
b.
State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
c.
School of Pharmacy, China Medical University, Shenyang 110122, China
d.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

wpzhang@bmi.ac.cn

xiaojunhai@139.com

bnuhuaxuelpy@163.com

zzbcaptain@aliyun.com

Received Date: 10 December 2024
Revised Date: 18 February 2025
Accepted Date: 20 February 2025
Available Online: 20 February 2025

Figures(5)

The von Hippel-Lindau tumor suppressor (VHL) has been extensively used to develop degraders targeting numerous proteins of interest. However, studies on the rational design of VHL-proteolysis-targeting chimeras (PROTACs) remain scarce. This study aimed to develop strategies to investigate VHL-recruiting PROTACs connecting with varying attachment sites on VHL ligands, which could be utilized for KRAS^G12C degraders development and expanded to additional targets. We developed a molecular dynamics (MD)-based strategy to explore the stability of ternary complexes induced by KRAS^G12C PROTACs with four distinct attachment sites of VH032. We found a potent degrader namely YN14-H, linked to hydroxyl group on VH032 benzene ring, exhibited the most superior ability of inducing ternary complexes, reflected by the lowest dissociation constant (K_d) for ternary complex induction and the highest AlphaScreen (AS)-based interaction. YN14-H inhibited cell growth with low nanomolar half maximal inhibitory concentration (IC₅₀) and half maximal degradation concentration (DC₅₀) values as well as >98% of maximum degradation (D_max) in NCI-H358 and MIA PaCa-2 cells harboring KRAS^G12C-mutation. Mechanistically, YN14-H significantly induced apoptosis and inhibited the migratory capacity. Notably, YN14-H demonstrated favorable pharmacokinetic properties and excellent antitumor activity in vivo. Furthermore, bromodomain-containing protein 7 (BRD7) and Bruton tyrosine kinase (BTK) degraders attached to distinct sites on VH032 further verified the rationality and universality of our MD-based strategies. Our findings demonstrated that YN14-H could serve as a promising candidate for the treatment of tumors with KRAS^G12C-mutation and present a strategy for the rational design of VHL-recruiting PROTACs that target additional proteins at distinct attachment sites.
- PROTACs,
- VHL,
- KRAS^G12C,
- Rational drug design,
- Molecular dynamics
1. [1]
  M. Toure, C.M. Crews, Angew. Chem. Int. Ed. 55 (2016) 1966–1973. doi: 10.1002/anie.201507978
2. [2]
  C. Pu, S. Wang, L. Liu, et al., Chin. Chem. Lett. 34 (2023) 107927. doi: 10.1016/j.cclet.2022.107927
3. [3]
  M. Békés, D.R. Langley, C.M. Crews, Nat. Rev. Drug Discov. 21 (2022) 181–200. doi: 10.1038/s41573-021-00371-6
4. [4]
  P. Li, C. Jia, Z. Fan, et al., Acta. Pharm. Sin. B 13 (2023) 2715–2735. doi: 10.1016/j.apsb.2023.01.014
5. [5]
  W. Zhang, P. Li, S. Sun, et al., Eur. J. Med. Chem. 238 (2022) 114509. doi: 10.1016/j.ejmech.2022.114509
6. [6]
  Y.R. Alugubelli, J. Xiao, K. Khatua, et al., J. Med. Chem. 67 (2024) 6495–6507. doi: 10.1021/acs.jmedchem.3c02416
7. [7]
  D. Grifagni, E. Lenci, A. De Santis, et al., ACS Med. Chem. Lett. 15 (2024) 250–257. doi: 10.1021/acsmedchemlett.3c00498
8. [8]
  X. Ren, L. Wang, L. Liu, J. Liu, Front. Immunol. 15 (2024) 1392546. doi: 10.3389/fimmu.2024.1392546
9. [9]
  P. Ottis, C.M. Crews, ACS Chem. Biol. 12 (2017) 892–898. doi: 10.1021/acschembio.6b01068
10. [10]
  J.S. Schneekloth Jr., F.N. Fonseca, M. Koldobskiy, et al., J. Am. Chem. Soc. 126 (2004) 3748–3754. doi: 10.1021/ja039025z
11. [11]
  M.J. Bond, L. Chu, D.A. Nalawansha, et al., ACS Central Sci. 6 (2020) 1367–1375. doi: 10.1021/acscentsci.0c00411
12. [12]
  F. Yang, Y. Wen, C. Wang, et al., Eur. J. Med. Chem. 230 (2022) 114088. doi: 10.1016/j.ejmech.2021.114088
13. [13]
  S. Jaime-Figueroa, A.D. Buhimschi, M. Toure, et al., Bioorg. Med. Chem. Lett. 30 (2020) 126877. doi: 10.1016/j.bmcl.2019.126877
14. [14]
  R. Gabizon, A. Shraga, P. Gehrtz, et al., J. Am. Chem. Soc. 142 (2020) 11734–11742. doi: 10.1021/jacs.9b13907
15. [15]
  V. Zoppi, S.J. Hughes, C. Maniaci, et al., J. Med. Chem. 62 (2019) 699–726. doi: 10.1021/acs.jmedchem.8b01413
16. [16]
  I.A. Prior, F.E. Hood, J.L. Hartley, Cancer Res. 80 (2020) 2969–2974. doi: 10.1158/0008-5472.can-19-3682
17. [17]
  J.M. Ostrem, K.M. Shokat, Nat. Rev. Drug Discov. 15 (2016) 771–785. doi: 10.1038/nrd.2016.139
18. [18]
  M.H. Hofmann, D. Gerlach, S. Misale, et al., Cancer Discov. 12 (2022) 924–937. doi: 10.1158/2159-8290.cd-21-1331
19. [19]
  N. Yang, Z. Fan, S. Sun, et al., Eur. J. Med. Chem. 261 (2023) 115857. doi: 10.1016/j.ejmech.2023.115857
20. [20]
  P. Li, X. Hu, Z. Fan, et al., J. Hematol. Oncol. 17 (2024) 77. doi: 10.1186/s13045-024-01592-z
21. [21]
  S.J. Hughes, A. Testa, N. Thompson, I. Churcher, Drug Discov. Today 26 (2021) 2889–2897. doi: 10.1016/j.drudis.2021.08.006
22. [22]
  B.E. Smith, S.L. Wang, S. Jaime-Figueroa, et al., Nat. Commun. 10 (2019) 131. doi: 10.26506/pharmhist.61.3-4.0131
23. [23]
  N.A. Zografou-Barredo, A.J. Hallatt, J. Goujon-Ricci, C. Cano, Bioorg. Med. Chem. 88-89 (2023) 117334. doi: 10.1016/j.bmc.2023.117334
24. [24]
  W. Li, J. Zhang, L. Guo, Q. Wang, J. Chem. Inf. Model. 62 (2022) 523–532. doi: 10.1021/acs.jcim.1c01150
25. [25]
  J. Zhang, Y. Cong, L. Duan, J.Z.H. Zhang, J. Chem. Inf. Model. 63 (2023) 5297–5308. doi: 10.1021/acs.jcim.3c00813
26. [26]
  K.K. Bhanja, M. Sharma, N. Patra, J. Phys. Chem. B 127 (2023) 10749–10765. doi: 10.1021/acs.jpcb.3c04337
27. [27]
  J. Yan, S. Sun, W. Zhang, et al., J. Cell. Biochem. 122 (2021) 1207–1215. doi: 10.1002/jcb.29941
28. [28]
  T. Bartoschik, A. Zoephel, K. Rumpel, et al., Methods. Mol. Biol. 2365 (2021) 115–133. doi: 10.1007/978-1-0716-1665-9_6
29. [29]
  K. Parikh, G. Banna, S.V. Liu, et al., J. Hematol. Oncol. 15 (2022) 152.
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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

Rational design of VHL-recruiting KRASG12C proteolysis-targeting chimeras based on molecular dynamics simulation

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通讯作者: 陈斌, bchen63@163.com

Rational design of VHL-recruiting KRAS^G12C proteolysis-targeting chimeras based on molecular dynamics simulation