Carboranylanilinoquinazoline EGFR-Inhibitors: Toward ‘Lead-to-Candidate’ Stage in the Drug-Development Pipeline

Abstract

Background: Carboranylanilinoquinazoline-hybrids, developed for boron neutron capture therapy, have demonstrated cytotoxicity against murine-glioma cells with EGFR-inhibition ability. In addition, their adequate aqueous/metabolic stabilities and ability to cross blood–brain barrier make them good leads as to become antiglioma drugs. Aim: Analyze drug-like properties of representative carboranylanilinoquinazolines. Materials & methods: To expand carboranylanilinoquinazolines therapeutic spectrum, we studied their ability to act against glioma-mammal cells, U-87 MG and other tyrosine kinase-overexpress cells, HT-29. Additionally, we predicted theoretically and studied experimentally drug-like properties, in other words, organization for economic cooperation and development-recommended toxicity-studies and, due to some aqueous-solubility problems, and vehicularization for oral and intravenous administrations. Conclusion: We have identified a promising drug-candidate with broad activity spectrum, appropriate drug-like properties, adequate toxicological behavior and able ability to be loaded in suitable vehicles.

Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity

“…Table 1 summarizes the in vitro activity of the parent Sun, Erl, and Lap tyrosine kinase receptor inhibitors and the most active compounds of each family of hybrids compounds derived from these TKRs inhibitors. The incorporation of boron cluster resulted in hybrid compounds, such as carboranes 1-3 ( Figure 1), with enhanced in vitro activity against TKR-overexpressing cells with respect to the corresponding parents [18][19][20][21][22]. In these studies, compound 1 stood out, especially against glioma cells, compared to Erl and Lap derivatives, i.e., 2 and 3, and compared to the rest of the Sun derivatives ( Table 1, Table S1).…”

“…All these indications foresee BNCT as an accessible leading-edge technology. (Sun), erlotinib (Erl), and lapatinib (Lap); and a previous hybrid TKI-boron cluster [18][19][20][21][22].…”

“…Regarding this subject, we have previously investigated and developed hybrid agents that provide dual therapeutic actions (chemotherapy plus BNCT), i.e., tyrosine kinase receptor inhibitors such as chemotherapeutics and boron clusters, as BNCT agents. The substructures derived of the TKRs inhibitors, which were combined with icosahedral boron clusters for potential use in BNCT, are sunitinib (Sun, Figure 1), erlotinib (Erl, Figure 1), and lapatinib (Lap, Figure 1) [18][19][20][21][22].…”

Ruthenium carboranyl complexes with 2,2′-bipyridine derivatives for potential bimodal therapy application

“…20,21 Besides, substituents can also be introduced with good control to at least a certain number of boron vertices, making the research in this area very versatile and attractive for BNCT. The icosahedral closo-C 2 B 10 H 12 carborane 22 and metallacarborane 23 [M(C 2 B 9 H 11 ) 2 ] À clusters are 3D aromatic moieties, possessing high symmetry and stability, 24 and generally low cytotoxicity, 25,26 being good candidates for BNCT. 25,[27][28][29] In this frame, several compositions for potential BNCT applications have been developed, [30][31][32][33][34][35] including high boron-loaded DNA-oligomers, 36 periphery-decorated and core-initiated borane polyanionic macromolecules, 37 peptide-cobalt bis(dicarbollide) conjugates, 38 nucleoside-boron cluster conjugates 39,40 and cholesterol-metallacarborane conjugates, 41 among others.…”

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

“…Cells 2020, 9, x FOR PEER REVIEW 11 of 19 Scheme 1. Synthetic procedures used to prepare the hybrids carboranyl-and cobaltabis(dicarbollide)-lapatinib-scaffold (18)(19)(20)(21)(22) and the bioisoster 23.…”