Closo-Carboranyl- and Metallacarboranyl [1,2,3]triazolyl-Decorated Lapatinib-Scaffold for Cancer Therapy Combining Tyrosine Kinase Inhibition and Boron Neutron Capture Therapy.

Marcos Couto,María García,María Dagrosa,Emiliano Trias,Francesc Teixidor,Silvia Thorp,Paula Curotto,Clara Viñas,Mariángeles Kovacs,Susana Nievas,Catalina Alamón,Hugo Cerecetto,Emiliano Pozzi

doi:10.3390/cells9061408

Abstract

One of the driving forces of carcinogenesis in humans is the aberrant activation of receptors; consequently, one of the most promising mechanisms for cancer treatment is receptor inhibition by chemotherapy. Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. Anti-tumor agents overcoming resistance and acting through two or more ways offer greater therapeutic benefits over single-mechanism entities. In this study, we report on a new family of bifunctional compounds that, offering the possibility of dual action (drug + radiotherapy combinations), may result in significant clinical benefits. This new family of compounds combines two fragments: the drug fragment is a lapatinib group, which inhibits the tyrosine kinase receptor activity, and an icosahedral boron cluster used as agents for neutron capture therapy (BNCT). The developed compounds were evaluated in vitro against different tyrosine kinase receptors (TKRs)-expressing tumoral cells, and in vitro–BNCT experiments were performed for two of the most promising hybrids, 19 and 22. We identified hybrid 19 with excellent selectivity to inhibit cell proliferation and ability to induce necrosis/apoptosis of glioblastoma U87 MG cell line. Furthermore, derivative 22, bearing a water-solubility-enhancing moiety, showed moderate inhibition of cell proliferation in both U87 MG and colorectal HT-29 cell lines. Additionally, the HT-29 cells accumulated adequate levels of boron after hybrids 19 and 22 incubations rendering, and after neutron irradiation, higher BNCT-effects than BPA. The attractive profile of developed hybrids makes them interesting agents for combined therapy.

Highlights

Tyrosine kinase receptors (TKRs) are transmembrane-type receptors with cytoplasmic tyrosine kinase domains, which transduce extracellular signals to a variety of intracellular signaling cascades involved in proliferation and differentiation of both normal and malignant cells [1]
We have demonstrated that the incorporation of the boron cluster has resulted in hybrids with enhanced and selective in vitro and in vivo anti-tumoral activities, i.e., compounds 1, 2, and 4 (Figure 1) [18,19,20,21]
The following two structural features are responsible for effective Lap EGFR interaction [37]: i) the quinazoline ring, via its nitrogens that establish hydrogen bonds to Met769 and Thr830, and sandwiching between Ala719 and Leu820; and ii) the fluorobenzyloxyphenylamino moiety that makes hydrophobic interactions in the back of the ATP binding site

Summary

Introduction

Tyrosine kinase receptors (TKRs) are transmembrane-type receptors with cytoplasmic tyrosine kinase domains, which transduce extracellular signals to a variety of intracellular signaling cascades involved in proliferation and differentiation of both normal and malignant cells [1]. TKRs are attractive targets for the development of therapeutic tools, for example, small inhibitors such as erlotinib (Erl)-targeting epidermal growth factor receptor (EGFR, ErbB1), and lapatinib (Lap) targeting EGFR and human epidermal growth factor receptor 2 (ErbB2, HER2) (Figure 1) [3,4,5]. Another anti-cancer strategy, boron neutron capture therapy (BNCT), has been recognized as a promising therapy for melanoma, locally malignant gliomas, and head and neck cancers [6,7,8,9,10]. BSH and its derivatives are of increasing interest as boron carriers for BNCT, due to the ability to deliver large amounts of 10 B atoms to tumor cells

Methods

Results

Conclusion