Theoretical and Natural Science
- The Open Access Proceedings Series for Conferences
Proceedings of the International Conference on Modern Medicine and Global Health (ICMMGH 2023)
Series Vol. 6 , 03 August 2023
Open
Access | Article
The role and efficacy of PROTAC in FLT3-mutated AML treatment
* Author to whom correspondence should be addressed.
Abstract
Small molecule Proteolysis Targeting Chimera (PROTAC) is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML). By activating the ubiquitination system, PROTAC can generate protein and kinase degradation upon FLT3 to perform outcomes of antiproliferative activities. The focus of this study revolves around the investigation of the efficacy of VHL and CRBN-based PROTAC on FLT3 degradation compared to conventional immunotherapy agents such as quizartinib. By assessing the performances of PROTAC on MOLM-14 and MV4-11 cells with other therapies, comparing both adverse effects and benefits could demonstrate crucial approaches to applying PROTAC for AML treatments. The VHL-recruiting PROTAC based on the modification of quizartinib has shown promising effects where FLT3 within MV4-11 injected athymic mice had experienced around a 60% of decrease. The CRBN-based degrader TL12-186, on the other hand, had also demonstrated antiproliferative outcomes where 14 out of 7559 proteins of the MOLM-14 cell have been successfully degraded, showing a more than 25% decrease. Even though there seem to be some improvements in the VHL-recruiting PROTAC compared to traditional immunotherapy agents like quizartinib, CRBN-mediated PROTAC has shown a relatively less significant result. Critiquing in a variety of aspects, quizartinib has demonstrated better performance in cell permeability, low nanomolecular concentration, and degradation. The significance of this study provides an overview of existing PROTAC technology that shows effects on the treatment of FLT3-mutated AML. Further studies may be conducted on the foundation of this study to demonstrate the enhancements of each modified PROTAC compared to existing therapies.
Keywords
PROTACs, FLT3 mutation, AML, quizartinib, TL12-186
References
1. Mendez LM, Posey RR, Pandolfi PP. The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy. Front Oncol. 2019;9:1162.
2. Řezníčková E, Krajčovičová S, Peřina M, Kovalová M, Soural M, Kryštof V. Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC). Eur J Med Chem. 2022;243:114792.
3. Sun X, Gao H, Yang Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4(1):64.
4. Schlenk RF, Döhner K, Krauter J, et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. N Engl J Med. 2008;358(18):1909-1918.
5. Burslem GM, Song J, Chen X, Hines J, Crews CM. Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion. J Am Chem Soc. 2018;140(48):16428-16432.
6. Pettersson M, Crews CM. PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future. Drug Discov Today Technol. 2019;31:15-27.
7. PROTACs and Targeted Protein Degradation. Biopharma PEG. Published June 29, 2020. Accessed March 6, 2023. https://www.biochempeg.com/article/116.html
8. Smith Y. Ubiquitination (Ubiquitylation). News-Medical. Published August 23, 2018. Accessed March 6, 2023. https://www.news-medical.net/life-sciences/Ubiquitination-(Ubiquitylation).aspx
9. Wang P, Xiao X, Zhang Y, et al. A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia. J Hematol OncolJ Hematol Oncol. 2021;14(1):105.
10. Xi M, Chen Y, Yang H, et al. Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation. Eur J Med Chem. 2019;174:159-180.
11. Huang HT, Dobrovolsky D, Paulk J, et al. A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. Cell Chem Biol. 2018;25(1):88-99.e6.
12. Matsuo Y, MacLeod R, Uphoff C, et al. Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). Leukemia. 1997;11(9):1469-1477.
13. Barouch-Bentov R, Sauer K. Mechanisms of drug resistance in kinases. Expert Opin Investig Drugs. 2011;20(2):153-208.
Data Availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
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- Volume Title
- Proceedings of the International Conference on Modern Medicine and Global Health (ICMMGH 2023)
- ISBN (Print)
- 978-1-915371-65-2
- ISBN (Online)
- 978-1-915371-66-9
- Published Date
- 03 August 2023
- Series
- Theoretical and Natural Science
- ISSN (Print)
- 2753-8818
- ISSN (Online)
- 2753-8826
- DOI
- 10.54254/2753-8818/6/20230233
- Copyright
- © 2023 The Author(s)
- Open Access
- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited