Development of PROTACS Degrading KRAS and SOS1

Overview

Journal Oncol Res

Specialty Oncology

Date 2024 Jul 26

PMID 39055890

Authors

Gerhard Hamilton

Marie-Therese Eggerstorfer

Sandra Stickler

Affiliations

Soon will be listed here.

Abstract

The Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity and compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

References

Depeille P, Henricks L, van de Ven R, Lemmens E, Wang C, Matli M . RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. Nat Cell Biol. 2015; 17(6):804-15. PMC: 4652934. DOI: 10.1038/ncb3175. View

Shang Y, Fu S, Hao Q, Ying H, Wang J, Shen T . Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions. Bioorg Chem. 2024; 144:107092. DOI: 10.1016/j.bioorg.2023.107092. View

Lai A, Crews C . Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2016; 16(2):101-114. PMC: 5684876. DOI: 10.1038/nrd.2016.211. View

Bond M, Chu L, Nalawansha D, Li K, Crews C . Targeted Degradation of Oncogenic KRAS by VHL-Recruiting PROTACs. ACS Cent Sci. 2020; 6(8):1367-1375. PMC: 7453568. DOI: 10.1021/acscentsci.0c00411. View

Ketcham J, Haling J, Khare S, Bowcut V, Briere D, Burns A . Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction. J Med Chem. 2022; 65(14):9678-9690. PMC: 9340770. DOI: 10.1021/acs.jmedchem.2c00741. View

Punekar S, Velcheti V, Neel B, Wong K . The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022; 19(10):637-655. PMC: 9412785. DOI: 10.1038/s41571-022-00671-9. View

Bery N, Miller A, Rabbitts T . A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. Nat Commun. 2020; 11(1):3233. PMC: 7319959. DOI: 10.1038/s41467-020-17022-w. View

Zhou C, Fan Z, Zhou Z, Li Y, Cui R, Liu C . Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations. J Med Chem. 2022; 65(5):3923-3942. DOI: 10.1021/acs.jmedchem.1c01774. View

Cieslak M, Slowianek M . Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges?. Pharmaceutics. 2023; 15(3). PMC: 10053963. DOI: 10.3390/pharmaceutics15030812. View

10.

Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y . Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol Cancer. 2022; 21(1):99. PMC: 8996410. DOI: 10.1186/s12943-021-01434-3. View

11.

Donovan K, Ferguson F, Bushman J, Eleuteri N, Bhunia D, Ryu S . Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell. 2020; 183(6):1714-1731.e10. PMC: 10294644. DOI: 10.1016/j.cell.2020.10.038. View

12.

Yang X, Yin H, Kim R, Fleming J, Xie H . Preclinical and Clinical Advances of Targeted Protein Degradation as a Novel Cancer Therapeutic Strategy: An Oncologist Perspective. Target Oncol. 2020; 16(1):1-12. DOI: 10.1007/s11523-020-00782-2. View

13.

Bond M, Crews C . Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem Biol. 2021; 2(3):725-742. PMC: 8190915. DOI: 10.1039/d1cb00011j. View

14.

Kortum K, Mai E, Hanafiah N, Shi C, Zhu Y, Bruins L . Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood. 2016; 128(9):1226-33. PMC: 5524534. DOI: 10.1182/blood-2016-02-698092. View

15.

Pedrucci F, Pappalardo C, Marzaro G, Ferri N, Ferlin A, De Toni L . Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening. Int J Mol Sci. 2022; 23(12). PMC: 9223854. DOI: 10.3390/ijms23126630. View

16.

Bekes M, Langley D, Crews C . PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022; 21(3):181-200. PMC: 8765495. DOI: 10.1038/s41573-021-00371-6. View

17.

Bartlett D, Gilbert A . Translational PK-PD for targeted protein degradation. Chem Soc Rev. 2022; 51(9):3477-3486. DOI: 10.1039/d2cs00114d. View

18.

Gooding S, Ansari-Pour N, Towfic F, Estevez M, Chamberlain P, Tsai K . Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood. 2021; 137(2):232-237. PMC: 7893409. DOI: 10.1182/blood.2020007081. View

19.

Skoulidis F, Li B, Dy G, Price T, Falchook G, Wolf J . Sotorasib for Lung Cancers with p.G12C Mutation. N Engl J Med. 2021; 384(25):2371-2381. PMC: 9116274. DOI: 10.1056/NEJMoa2103695. View

20.

Han X, Zhao L, Xiang W, Qin C, Miao B, Xu T . Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. J Med Chem. 2019; 62(24):11218-11231. DOI: 10.1021/acs.jmedchem.9b01393. View