Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)–mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor–associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.
We
report a photoredox-catalyzed α-amino C–H arylation
reaction of highly substituted piperidine derivatives with electron-deficient
cyano(hetero)arenes. The scope and limitations of the reaction were
explored, with piperidines bearing multiple substitution patterns
providing the arylated products in good yields and with high diastereoselectivity.
To probe the mechanism of the overall transformation, optical and
fluorescent spectroscopic methods were used to investigate the reaction.
By employing flash-quench transient absorption spectroscopy, we were
able to observe electron transfer processes associated with radical
formation beyond the initial excited-state Ir(ppy)3 oxidation.
Following the rapid and unselective C–H arylation reaction,
a slower epimerization occurs to provide the high diastereomer ratio
observed for a majority of the products. Several stereoisomerically
pure products were resubjected to the reaction conditions, each of
which converged to the experimentally observed diastereomer ratios.
The observed distribution of diastereomers corresponds to a thermodynamic
ratio of isomers based upon their calculated relative energies using
density functional theory (DFT).
An enantioconvergent Friedel-Crafts alkylation of indoles with donor-acceptor cyclopropanes is described. The reaction is catalyzed by pybox•MgI2 and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT).
A dynamic kinetic resolution of β-halo
α-keto esters
in an asymmetric homoenolate reaction is described. A chiral N-hetereocyclic carbene catalyzes the a3 →
d3-umpolung addition of α,β-enals
to racemic α-keto esters, forming γ-butyrolactones with
three contiguous stereocenters. The addition occurs with high regio-,
diastereo-, and enantiocontrol. This methodology constitutes an intermolecular
DKR process to set three stereocenters during the key bond forming
event.
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