Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• SRC is a key regulator in signaling pathways implicated in cancer development.
• Existing FDA-approved SRC inhibitors are non-selective, targeting multiple kinases.
• Developing selective SRC inhibitors remains a significant challenge in cancer therapy.

Purpose of the Study:

• To design and synthesize a selective covalent inhibitor targeting SRC.
• To overcome the limitations of non-selective SRC inhibitors.
• To evaluate the efficacy of the novel inhibitor in preclinical cancer models.

Main Methods:

• Utilized a promiscuous covalent kinase inhibitor (SM1-71) as a starting scaffold.
• Developed a selective covalent inhibitor, compound 15a, by targeting SRC's cysteine 277.
• Assessed compound 15a's selectivity against other kinases (TAK1, FGFR1) and its inhibitory effects in vitro and in vivo.
• Evaluated antiproliferative effects in non-small cell lung cancer cell lines.

Main Results:

• Compound 15a selectively inhibited SRC, discriminating it from other covalent targets of SM1-71.
• 15a demonstrated sustained inhibition of SRC signaling both in vitro and in vivo.
• The inhibitor exhibited potent antiproliferative activity in non-small cell lung cancer cell lines with SRC activation.

Conclusions:

• Targeting cysteine 277 on SRC's P-loop with a covalent inhibitor is a viable strategy.
• Compound 15a represents a promising selective SRC inhibitor for further drug development.
• This approach holds potential for treating cancers driven by SRC activation, such as non-small cell lung cancer.