Drug–drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

Abstract

Controlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug–drug conjugates (DDCs) by combining the MEK inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. These DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and anticancer efficacies comparable to those of trametinib. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers.

Strain-Based Design, Direct Macrocyclization, and Metal Complexation of Thiazole-Containing Calix[3]pyrrole Analogues

“…According to the theoretical calculations, thiazolecontaining derivatives 2 and 5 were found to be the most feasible among the evaluated compounds 1-5. Given synthetic availability of furan precursor 6, [14] we examined direct macrocyclization synthesis of 5 using a Hantzsch-type thiazole formation reaction. [15] To our delight, condensation reaction between 6 and 2,2-dimethylpropanebis(thioamide) (7) [16] in refluxing ethanol gave calix[1]furan[2]thiazole (5) in 60% yield (Scheme 1), along with a double sized macrocycle, calix[2]furan [4]thiazole in 16% yield (see SI).…”