Modulation of ABCG2 Transporter Activity by Ko143 Derivatives.

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• ABCG2 is a crucial multidrug transporter involved in xenobiotic protection, drug pharmacokinetics, and cancer multidrug resistance.
• Understanding ABCG2 regulation is vital for improving drug efficacy and overcoming resistance.

Purpose of the Study:

• To investigate the structure-activity relationships of tetracyclic fumitremorgin C analogs as ABCG2 inhibitors.
• To elucidate the molecular mechanisms underlying ABCG2 inhibition by these compounds.

Main Methods:

• Synthesis and in vitro evaluation of Ko143 derivatives.
• High-resolution cryo-electron microscopy (cryo-EM) for structural determination.
• Computational analyses including molecular dynamics simulations and binding free energy calculations.

Main Results:

• Closed-ring, tetracyclic analogs were potent ABCG2 inhibitors, while ring-opened derivatives lost activity.
• The inhibitor MZ82 exhibited a unique binding pose, inducing partial closure of transmembrane domains and increased nucleotide-binding domain flexibility.
• Structural modifications significantly altered inhibitory potency and induced substrate-like conformational changes.

Conclusions:

• Minor structural changes in Ko143 derivatives can drastically impact ABCG2 inhibition and conformational dynamics.
• The potent inhibitor AZ99 demonstrates potential for improved in vivo stability.
• These findings provide a foundation for designing novel ABCG2 modulators for therapeutic applications.