Chimeric small molecule therapeutics
Chimeric small molecule therapeutics are a class of drugs designed with multiple active domains to operate outside of the typical protein inhibition model. While most small molecule drugs inhibit target proteins by binding their active site, chimerics form protein-protein ternary structures to induce degradation or, less frequently, other protein modifications.
Background
editSmall molecule drugs, compounds typically <1 kD in mass, comprise a large portion of the therapeutic market.[1] These drugs usually operate by agonizing or antagonizing the active site on a disease-linked protein of interest, though allosteric regulation is possible.[2] With an estimated 93% of the human proteome lacking druggable binding sites,[3] methods have been developed to modulate protein activity through binding of any available site rather than only the active site. These drugs contain a target protein binding warhead in addition to a linker-separated active domain. This domain may recruit a second protein to the proximity, induce protease-mediated degradation, or recruit a kinase for directed phosphorylation, among other functions.[4] These drugs expand both the mechanism of action for small molecule therapeutics and the pool of potential protein targets.[5]
Proteolysis-targeting chimeras
editProteolysis-targeting chimeras (PROTACs) were first reported by Kathleen Sakamoto, Craig Crews, and Raymond Deshaies in 2001. A chimeric molecule consisting of ovalicin (a MetAP-2 small molecule inhibitor) and IκBα phosphopeptide (a recruiter of the SCFβ-TRCP E3 ligase complex) separated by a linker was constructed and shown to induce MetAP-2 degradation in in vitro cell models. Further study confirmed that E3 ligase-mediated ubiquitination and subsequent proteasome degradation was responsible for reduced MetAP-2 levels.[6] Continued work on this system by Craig Crews and others has expanded the potential pool of E3 ligases and degradation targets with Arvinas Inc. founded in 2013 to bring PROTAC drugs to market.[7] As of April 2023, Arvinas has one drug in Stage 3 clinical trials (ARV-471, an estrogen receptor degrader), and two drugs in Stage 2 clinical trials (androgen receptor degraders ARV-110 and ARV-766) for treatment of breast and prostate cancer, respectively.[8] Arvinas released Phase 2 clinical trial results for ARV-471 in December, 2022 reporting a clinical benefit rate of 40% in CDK4/6 inhibitor-pretreated patients and an absence of dose-limiting toxicities.[9]
Hydrophobic tag degradation
editHydrophobic tag degraders contain a binding domain in addition to a linker-separated hydrophobic moiety, such as adamantyl, to induce protein degradation. As exposed hydrophobicity is characteristic of protein misfolding,[10] the native cell proteasome may recognize and degrade proteins tagged with the hydrophobic moiety. Taavi Neklesa and Craig Crews first reported hydrophobic tag degradation in 2011 as a tool to probe protein function in conjunction with cognate HaloTag fusion proteins.[11] This principle has also been further used to effectively degrade transcription factors[12] (a traditionally difficult class to drug[13]) and cancer-linked EZH2 in in vitro models.[14] As of yet, no drug candidates have been publicly identified making use of this technology.
Additional use cases
editLysosome-targeting chimeras (LYTACs) have been developed, combining target-binding compounds or antibodies and glycopeptide ligands to stimulate the lysosomal degradation pathway. Unlike the proteasome pathway, this enables the targeted degradation of extracellular and membrane-bound proteins in addition to cytoplasmic ones.[15] Autophagy-targeting chimeras (AUTACs) can be employed to degrade proteins as well as protein aggregates and organelles.[16] AUTAC degradation tags are typically derived from guanine though the particular mechanism of action is still unclear.[17] Autophagosome-tethering compounds (ATTECs) mimic this strategy, directly appending a target protein to the autophagosome membrane for degradation absent the use of a linker.[18] Phosphorylation-inducing chimeric small molecules (PHICS) employ the warhead-linker-recruiter structure to direct phosphorylation of a given target by proximity to a desired kinase. This technique does not necessarily involve protein degradation and may instead be used to modulate protein function to direct or inhibit certain pathways.[19] Further work in the Crews Lab has used chimeric oligonucleotides, the dCas9 protein, and chimeric small molecules to create the TRAFTAC system for generalizable transcription factor degradation.[20]
Advantages
editThe ability to inhibit or modify enzyme function absent a catalytic pocket binding site target greatly expands the potentially druggable portion of the proteome.[21] Furthermore, most classes of chimeric small molecules can act on many targets over their life cycle,[22] lowering the effective dose compared to traditional inhibitors that act only on one protein at a time.[23] These therapeutics provide an alternative mechanism of action that may be useful as a combination therapy in diseases where drug resistance is a concern.[24] Chimeric drug activity is also highly dependent on distance between targeted proteins[25] allowing effect to be effectively tuned through optimization of the linker structure.
Challenges
editThe existence of two or more binding domains increases the difficulty of synthesis for chimeric molecules. Each component must be discovered, optimized, and synthesized in such a way that they can be linked together, driving up cost relative to single-domain inhibitors. The large size of chimeric molecules (typically 700-1100 Da) makes effective delivery difficult and increases complexity in pharmacokinetic design.[26][27] Care must be taken to ensure that the molecule is capable of passing through the cell membrane[28] and subsisting long enough to have therapeutic effect. Additionally, protein-protein ternary complexes are generally unstable, adding to the difficulty of chimeric drug design[29]
References
edit- ^ Veber, Daniel F.; Johnson, Stephen R.; Cheng, Hung-Yuan; Smith, Brian R.; Ward, Keith W.; Kopple, Kenneth D. (2002-06-01). "Molecular Properties That Influence the Oral Bioavailability of Drug Candidates". Journal of Medicinal Chemistry. 45 (12): 2615–2623. doi:10.1021/jm020017n. ISSN 0022-2623. PMID 12036371. Retrieved 2023-04-14.
- ^ Li, Qingxin; Kang, CongBao (2020-07-24). "Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery". International Journal of Molecular Sciences. 21 (15): 5262. doi:10.3390/ijms21155262. ISSN 1422-0067. PMC 7432558. PMID 32722222.
- ^ Kana, Omar; Brylinski, Michal (May 2019). "Elucidating the druggability of the human proteome with eFindSite". Journal of Computer-aided Molecular Design. 33 (5): 509–519. Bibcode:2019JCAMD..33..509K. doi:10.1007/s10822-019-00197-w. ISSN 0920-654X. PMC 6516084. PMID 30888556.
- ^ Li, Haobin; Dong, Jinyun; Cai, Maohua; Xu, Zhiyuan; Cheng, Xiang-Dong; Qin, Jiang-Jiang (2021-09-06). "Protein degradation technology: a strategic paradigm shift in drug discovery". Journal of Hematology & Oncology. 14 (1): 138. doi:10.1186/s13045-021-01146-7. ISSN 1756-8722. PMC 8419833. PMID 34488823. S2CID 237418638.
- ^ Li, Haobin; Dong, Jinyun; Cai, Maohua; Xu, Zhiyuan; Cheng, Xiang-Dong; Qin, Jiang-Jiang (2021-09-06). "Protein degradation technology: a strategic paradigm shift in drug discovery". Journal of Hematology & Oncology. 14 (1): 138. doi:10.1186/s13045-021-01146-7. ISSN 1756-8722. PMC 8419833. PMID 34488823. S2CID 237418638.
- ^ Sakamoto, Kathleen M.; Kim, Kyung B.; Kumagai, Akiko; Mercurio, Frank; Crews, Craig M.; Deshaies, Raymond J. (2001-07-17). "Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8554–8559. Bibcode:2001PNAS...98.8554S. doi:10.1073/pnas.141230798. ISSN 0027-8424. PMC 37474. PMID 11438690.
- ^ Bouchie, Aaron; Allison, Malorye; Webb, Sarah; DeFrancesco, Laura (March 2014). "Nature Biotechnology's academic spinouts of 2013". Nature Biotechnology. 32 (3): 229–238. doi:10.1038/nbt.2846. ISSN 1546-1696. PMID 24727773. S2CID 692896. Retrieved 2023-04-14.
- ^ "PROTAC Protein Degrader Pipeline | Arvinas". Retrieved 2023-04-14.
- ^ "Pfizer Strengthens Cancer Standing with Protein Degrader Collaboration". BioSpace. Retrieved 2023-04-14.
- ^ Fredrickson, Eric K.; Rosenbaum, Joel C.; Locke, Melissa N.; Milac, Thomas I.; Gardner, Richard G. (2011-07-01). "Exposed hydrophobicity is a key determinant of nuclear quality control degradation". Molecular Biology of the Cell. 22 (13): 2384–2395. doi:10.1091/mbc.E11-03-0256. ISSN 1059-1524. PMC 3128539. PMID 21551067.
- ^ Neklesa, Taavi K.; Tae, Hyun Seop; Schneekloth, Ashley R.; Stulberg, Michael J.; Corson, Timothy W.; Sundberg, Thomas B.; Raina, Kanak; Holley, Scott A.; Crews, Craig M. (2011-07-03). "Small-Molecule Hydrophobic Tagging Induced Degradation of HaloTag Fusion Proteins". Nature Chemical Biology. 7 (8): 538–543. doi:10.1038/nchembio.597. ISSN 1552-4450. PMC 3139752. PMID 21725302.
- ^ Choi, So Ra; Wang, Hee Myeong; Shin, Min Hyeon; Lim, Hyun-Suk (2021-06-15). "Hydrophobic Tagging-Mediated Degradation of Transcription Coactivator SRC-1". International Journal of Molecular Sciences. 22 (12): 6407. doi:10.3390/ijms22126407. ISSN 1422-0067. PMC 8232704. PMID 34203850.
- ^ Lambert, Samuel A.; Jolma, Arttu; Campitelli, Laura F.; Das, Pratyush K.; Yin, Yimeng; Albu, Mihai; Chen, Xiaoting; Taipale, Jussi; Hughes, Timothy R.; Weirauch, Matthew T. (2018-02-08). "The Human Transcription Factors". Cell. 172 (4): 650–665. doi:10.1016/j.cell.2018.01.029. ISSN 0092-8674. PMID 29425488. S2CID 3599827. Retrieved 2023-04-14.
- ^ Ma, Anqi; Stratikopoulos, Elias; Park, Kwang-Su; Wei, Jieli; Martin, Tiphaine C.; Yang, Xiaobao; Schwarz, Megan; Leshchenko, Violetta; Rialdi, Alexander; Dale, Brandon; Lagana, Alessandro; Guccione, Ernesto; Parekh, Samir; Parsons, Ramon; Jin, Jian (February 2020). "Discovery of a first-in-class EZH2 selective degrader". Nature Chemical Biology. 16 (2): 214–222. doi:10.1038/s41589-019-0421-4. ISSN 1552-4469. PMC 6982609. PMID 31819273.
- ^ Banik, Steven; Pedram, Kayvon; Wisnovsky, Simon; Riley, Nicholas; Bertozzi, Carolyn (2019). "Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins | Biological and Medicinal Chemistry". ChemRxiv. Cambridge Open Engage. doi:10.26434/chemrxiv.7927061.v1. Retrieved 2023-04-14.
- ^ Takahashi, Daiki; Moriyama, Jun; Nakamura, Tomoe; Miki, Erika; Takahashi, Eriko; Sato, Ayami; Akaike, Takaaki; Itto-Nakama, Kaori; Arimoto, Hirokazu (2019-12-05). "AUTACs: Cargo-Specific Degraders Using Selective Autophagy". Molecular Cell. 76 (5): 797–810.e10. doi:10.1016/j.molcel.2019.09.009. ISSN 1097-4164. PMID 31606272. S2CID 204546213.
- ^ Ding, Yu; Fei, Yiyan; Lu, Boxun (July 2020). "Emerging New Concepts of Degrader Technologies". Trends in Pharmacological Sciences. 41 (7): 464–474. doi:10.1016/j.tips.2020.04.005. ISSN 1873-3735. PMC 7177145. PMID 32416934.
- ^ Li, Zhaoyang; Zhu, Chenggang; Ding, Yu; Fei, Yiyan; Lu, Boxun (January 2020). "ATTEC: a potential new approach to target proteinopathies". Autophagy. 16 (1): 185–187. doi:10.1080/15548627.2019.1688556. ISSN 1554-8635. PMC 6984452. PMID 31690177.
- ^ Siriwardena, Sachini U.; Munkanatta Godage, Dhanushka N. P.; Shoba, Veronika M.; Lai, Sophia; Shi, Mengchao; Wu, Peng; Chaudhary, Santosh K.; Schreiber, Stuart L.; Choudhary, Amit (2020-08-19). "Phosphorylation-Inducing Chimeric Small Molecules". Journal of the American Chemical Society. 142 (33): 14052–14057. doi:10.1021/jacs.0c05537. ISSN 0002-7863. PMID 32787262. S2CID 221125004. Retrieved 2023-04-14.
- ^ Samarasinghe, Kusal T. G.; Jaime-Figueroa, Saul; Burgess, Michael; Nalawansha, Dhanusha A.; Dai, Katherine; Hu, Zhenyi; Bebenek, Adrian; Holley, Scott A.; Crews, Craig M. (2021-05-20). "Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras". Cell Chemical Biology. 28 (5): 648–661.e5. doi:10.1016/j.chembiol.2021.03.011. ISSN 2451-9448. PMC 8524358. PMID 33836141.
- ^ Lu, Bin; Ye, Jianpin (October 2021). "Commentary: PROTACs make undruggable targets druggable: Challenge and opportunity". Acta Pharmaceutica Sinica B. 11 (10): 3335–3336. doi:10.1016/j.apsb.2021.07.017. ISSN 2211-3835. PMC 8546888. PMID 34729320.
- ^ Békés, Miklós; Langley, David R.; Crews, Craig M. (March 2022). "PROTAC targeted protein degraders: the past is prologue". Nature Reviews Drug Discovery. 21 (3): 181–200. doi:10.1038/s41573-021-00371-6. ISSN 1474-1784. PMC 8765495. PMID 35042991.
- ^ Yao, Tingting; Xiao, Heng; Wang, Hong; Xu, Xiaowei (2022-09-07). "Recent Advances in PROTACs for Drug Targeted Protein Research". International Journal of Molecular Sciences. 23 (18): 10328. doi:10.3390/ijms231810328. ISSN 1422-0067. PMC 9499226. PMID 36142231.
- ^ Burke, Matthew R.; Smith, Alexis R.; Zheng, Guangrong (2022). "Overcoming Cancer Drug Resistance Utilizing PROTAC Technology". Frontiers in Cell and Developmental Biology. 10: 872729. doi:10.3389/fcell.2022.872729. ISSN 2296-634X. PMC 9083012. PMID 35547806.
- ^ Cyrus, Kedra; Wehenkel, Marie; Choi, Eun-Young; Han, Hyeong-Jun; Lee, Hyosung; Swanson, Hollie; Kim, Kyung-Bo (February 2011). "Impact of linker length on the activity of PROTACs". Molecular BioSystems. 7 (2): 359–364. doi:10.1039/c0mb00074d. ISSN 1742-2051. PMC 3835402. PMID 20922213.
- ^ Cantrill, Carina; Chaturvedi, Prasoon; Rynn, Caroline; Petrig Schaffland, Jeannine; Walter, Isabelle; Wittwer, Matthias B. (2020-06-01). "Fundamental aspects of DMPK optimization of targeted protein degraders". Drug Discovery Today. 25 (6): 969–982. doi:10.1016/j.drudis.2020.03.012. ISSN 1359-6446. PMID 32298797. S2CID 215803460. Retrieved 2023-04-14.
- ^ Pike, Andy; Williamson, Beth; Harlfinger, Stephanie; Martin, Scott; McGinnity, Dermot F. (2020-10-01). "Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective". Drug Discovery Today. 25 (10): 1793–1800. doi:10.1016/j.drudis.2020.07.013. ISSN 1359-6446. PMID 32693163. S2CID 220699596. Retrieved 2023-04-14.
- ^ Klein, Victoria G.; Townsend, Chad E.; Testa, Andrea; Zengerle, Michael; Maniaci, Chiara; Hughes, Scott J.; Chan, Kwok-Ho; Ciulli, Alessio; Lokey, R. Scott (10 September 2020). "Understanding and Improving the Membrane Permeability of VH032-Based PROTACs | ACS Medicinal Chemistry Letters". ACS Medicinal Chemistry Letters. 11 (9): 1732–1738. doi:10.1021/acsmedchemlett.0c00265. PMC 7488288. PMID 32939229.
- ^ Weiss, Dahlia R.; Bortolato, Andrea; Sun, Yongnian; Cai, Xianmei; Lai, Chon; Guo, Sixuan; Shi, Lihong; Shanmugasundaram, Veerabahu (2023-04-10). "On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations". Journal of Chemical Information and Modeling. 63 (8): 2382–2392. doi:10.1021/acs.jcim.2c01386. ISSN 1549-9596. PMID 37037192. S2CID 258061404. Retrieved 2023-04-14.