Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK)
family
of receptor tyrosine kinases that are aberrantly expressed and have
been implicated as therapeutic targets in a wide variety of human
tumors. Dual MERTK and AXL inhibition could provide antitumor action
mediated by both direct tumor cell killing and modulation of the innate
immune response in some tumors such as nonsmall cell lung cancer.
We utilized our knowledge of MERTK inhibitors and a structure-based
drug design approach to discover a novel class of macrocyclic dual
MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar
activity against both MERTK and AXL and good selectivity over TYRO3
and FLT3. Its target engagement and selectivity were also confirmed
by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and
long half-life) and mediated antitumor activity against lung cancer
cell lines, indicating its potential as a therapeutic agent.