Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876

Area of Science:

• Oncology
• Biochemistry
• Medicinal Chemistry

Background:

• The Warburg effect describes increased glucose consumption in tumors, driven by the glucose transporter GLUT1.
• Targeting GLUT1 is a strategy for cancer therapy, but requires high selectivity to avoid inhibiting other vital GLUT family members.
• Few selective small-molecule GLUT1 inhibitors have been developed.

Purpose of the Study:

• To identify a small molecule inhibitor with high potency and selectivity for GLUT1.
• To develop a therapeutic agent that targets tumor-specific glucose metabolism.

Main Methods:

• A high-throughput screen of approximately 3 million compounds was conducted.
• Structure-activity relationship studies were performed on identified N-(1H-pyrazol-4-yl)quinoline-4-carboxamides.
• In vitro and in vivo assays were used to evaluate compound efficacy, selectivity, metabolic stability, and bioavailability.

Main Results:

• N-(1H-pyrazol-4-yl)quinoline-4-carboxamides emerged as a promising scaffold.
• Single-digit nanomolar inhibitors with >100-fold selectivity against GLUT2, GLUT3, and GLUT4 were achieved.
• The lead compound, BAY-876, demonstrated good in vitro metabolic stability and high in vivo oral bioavailability.

Conclusions:

• BAY-876 is a potent and selective GLUT1 inhibitor with favorable pharmacokinetic properties.
• This compound represents a promising therapeutic candidate for targeting cancer metabolism via GLUT1 inhibition.
• Further development of BAY-876 could lead to novel cancer treatments exploiting the Warburg effect.