Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer

Multitarget medications represent an appealing therapy
against
the disease with multifactorial abnormalitiescancer. Therefore,
simultaneously targeting son of sevenless 1 (SOS1) and epidermal growth
factor receptor (EGFR), two aberrantly expressed proteins crucial
for the oncogenesis and progression of prostate cancer, may achieve
active antitumor effects. Here, we discovered dual SOS1/EGFR-targeting
compounds via pharmacophore-based docking screening. The most prominent
compound SE-9 exhibited nanomolar inhibition activity
against both SOS1 and EGFR and efficiently suppressed the phosphorylation
of ERK and AKT in prostate cancer cells PC-3. Cellular assays also
revealed that SE-9 displayed strong antiproliferative
activities through diverse mechanisms, such as induction of cell apoptosis
and G1 phase cell cycle arrest, as well as reduction of angiogenesis
and migration. Further in vivo findings showed that SE-9 potently inhibited tumor growth in PC-3 xenografts without
obvious toxicity. Overall, SE-9 is a novel dual-targeting
SOS1/EGFR inhibitor that represents a promising treatment strategy
for prostate cancer.