Generating Selective Leads for Mer Kinase InhibitorsExample of a Comprehensive Lead-Generation Strategy

Mer
is a member of the TAM (Tyro3, Axl, Mer) kinase family that
has been associated with cancer progression, metastasis, and drug
resistance. Their essential function in immune homeostasis has prompted
an interest in their role as modulators of antitumor immune response
in the tumor microenvironment. Here we illustrate the outcomes of
an extensive lead-generation campaign for identification of Mer inhibitors,
focusing on the results from concurrent, orthogonal high-throughput
screening approaches. Data mining, HT (high-throughput), and DECL
(DNA-encoded chemical library) screens offered means to evaluate large
numbers of compounds. We discuss campaign strategy and screening outcomes,
and exemplify series resulting from prioritization of hits that were
identified. Concurrent execution of HT and DECL screening successfully
yielded a large number of potent, selective, and novel starting points,
covering a range of selectivity profiles across the TAM family members
and modes of kinase binding, and offered excellent start points for
lead development.