PROTACs · Design, synthesis and biological evaluation of PROteolysis-TArgeting Chimeric (PROTAC) molecules as anticancer agents

Design, synthesis and biological evaluation of PROteolysis-TArgeting Chimeric (PROTAC) molecules as anticancer agents

Cancer diseases represent critical medical challenges. According to the recent estimates, 1 958 310 new cancer cases and 609 820 cancer deaths are projected to occur in the United States in 2023 [1]. On the other hand, 2 740 000 new cancer cases and 1 290 000 cancer-related deaths were detected in European Union in 2022 [2]. These figures underline that tumours remain one of the leading causes of death worldwide. Traditional anticancer drug design based on small molecules continues to be a powerful strategy for the development of novel chemotherapeutics. However, these anticancer therapies are facing major problems such as drug resistance, especially in advanced cancers. Therefore, in this project we decided to develop new series of PROteolysis-TArgeting Chimerics (PROTACs). It is worth noting that recently PROTACs have become a promising approach to overcome resistance since they act degrading instead of inhibiting the target with the advantage of reducing the systemic drug exposure and to counteract the protein expression that often accompanies inhibition of protein function [3,4]. Main objective of the project The main goal of the project was to develop new PROTACs targeting several enzymes, including histone deacetylases (HDACs), protein kinase 2 (CK2) and aromatase (AROM), all of which play crucial roles in cancer development and progression. Taking advantage of the host group´s experience in developing dual inhibitors for CK2/HDACs [5,6], we decided to synthesise PROTACs that simultaneously target both enzymes. To date, the reasearcher has successfully synthesized two different series of dual CK2/HDACs PROTACs based on the structure of CX-4945 (a potent CK2 inhibitor). These PROTACs were made by adding a moiety responsible for the action on HDACs to the CK2 ligand and connecting them to a Cereblon (CRBN) ligase recruiter through a linker of different lengths. Currently, we are actively evaluating the degradation capabilities of these newly synthesised CK2/HDACs PROTACs. In addition, during his research, the researcher has successfully synthesised two different series of novel PROTACs targeting AROM. The structure of these new potential AROM degraders was based on Aminoglutethimide, which is a first-generation AROM inhibitor [7]. These AROM-PROTACs were connected to two different E3 ligase recruiters, recognised by CRBN and von Hippel-Lindau (VHL) ligases, via variable-length linkers. Like the CK2/HDACs-PROTACs, the newly synthesised AROM-PROTACs are being evaluated biologically. Importantly, these types of PROTACs, belonging to both the CK2/HDACs and AROM classes, have not been previously described in the literature. For this reason, we are considering the possibility of applying for a patent after confirming their degradation capacity. Additional objective Since PROTACs often do not comply with the ¨Lipinski´s rule of five¨, their clinical applications may be limited due to their unfavorable pharmacokinetic properties and difficulties in crossing biological membranes. In light of these considerations, the researcher has devised synthetic methods for coupling the compounds with a folic acid (FA) molecule, which can serve as a natural carrier of biologically active substances, addressing their permeability limitations. So far, the researcher has synthesized FCs of CX-4945 and Aminoglutethimide, both of which are also used as cores of the PROTACs we have developed. Given the presence of the same functional groups, this strategy may be easily applied to obtain FCs from the synthesised PROTACs, with the aim of addressing issues related to the uptake of the compounds by cancer cells if detected. Furthermore, the synthesis of FCs from PROTACs promises to produce compounds with better activity and lower toxicity, a goal we hope to achieve in the future. [1] Siegel, R.L.; Miller, K.D.; Wagle, N.S.; et al.; CACancer J. Clin. 2023, 73, 17. [2] https://joint-research-centre.ec.europa.eu/jrc-news-and-updates/cancer-cases-and-deaths-rise-eu-2023-10-02_en, access: 8th November, 2023. [3] Li, M.; Zhi, Y.; Liu, B.; et al.; J. Med. Chem. 2023, 66, 2308. [4] Han, X.; Sun, Y.; MedComm. 2023, 4, e290. [5] Martinez, R.; Di Geronimo, B.; Pastor, M.; et al.; Molecules, 2020, 25. [6] Rangasamy, L.; Ortin, I.; Zapico, J.M.; et al.; ACS Med. Chem. Lett., 2020, 11, 713. [7] Sainsbury, R. Cancer Treat. Rev. 2013, 39, 507-517.

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