Bispecific
degraders (PROTACs) of ERα are expected to be
advantageous over current inhibitors of ERα signaling (aromatase
inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information
from DNA-encoded chemical library (DECL) screening provides a method
to identify novel PROTAC binding features as the linker positioning,
and binding elements are determined directly from the screen. After
screening ∼120 billion DNA-encoded molecules with ERα
WT and 3 gain-of-function (GOF) mutants, with and without estradiol
to identify features that enrich ERα competitively, the off-DNA
synthesized small molecule exemplar 7 exhibited nanomolar
ERα binding, antagonism, and degradation. Click chemistry synthesis
on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα,
with PROTACs 18 and 21 inhibiting ER+ MCF7
tumor growth in a mouse xenograft model of breast cancer. This study
validates this approach toward identifying novel bispecific degrader
leads from DECL screening with minimal optimization.
Inhibition
of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate
the accumulation of toxic oxalate that results from reduced activity
of alanine–glyoxylate aminotransferase (AGXT) in primary hyperoxaluria
1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided
two novel chemical series of potent HAO1 inhibitors, represented by
compounds 3–6. Compound 5 was further optimized via various structure–activity relationship
(SAR) exploration methods to 29, a compound with improved
potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic
(PK) properties. Since carboxylic acid-containing compounds are often
poorly permeable and have potential active glucuronide metabolites,
we undertook a brief, initial exploration of acid replacements with
the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based
drug design initiated with Compound 5 led to the identification
of a nonacid inhibitor of HAO1, 31, which has weaker
potency and increased permeability.
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