Abstract 3842: Berberine recognition of the dGMP-bound PDGFR-β promoter G-quadruplex: Structural insight into specific drug targeting

PDGFR-β (Platelet-Derived Growth Factor Receptor beta) is a receptor tyrosine kinase whose overexpression drives the progression and metastasis of many cancers. It is an established anticancer target and PDGFR-β inhibition via kinase inhibitors has been actively sought-after. However, PDGFR-β kinase inhibitors often lack specificity. The PDGFR-β gene promoter forms DNA G-quadruplexes that are transcription silencer whose stabilization by small molecules represses PDGFR-β expression. Therefore, targeting PDGFR-β promoter G-quadruplexes for transcriptional silencing is a promising alternative strategy for cancer therapy. G-quadruplex is an exciting family of non-canonical DNA secondary structures. DNA G-quadruplex within the PDGFR-β gene promoter forms novel vacancy pockets (vG4) that can be filled-in by guanine metabolites such as dGMP and cGMP. This presents an attractive target for small molecule targeting. Herein, we present the binding of the natural product berberine with the unique PDGFR-β dGMP-vG4 binary complex to form a novel ternary complex, the first case observed in DNA G-quadruplexes. Using circular dichroism, fluorescence, and nuclear magnetic resonance (NMR) spectroscopy, we demonstrated that berberine binds with high affinity and strongly stabilizes the dGMP-fill-in PDGFR-β vG4. Our determined high-resolution NMR structure of this ternary complex in K+-containing solution reveals a 2:1 binding stoichiometry of berberine to the dGMP-fill-in PDGFR-β vG4. Significantly, one berberine directly stacks upon and extensively covers the dGMP. This direct binding mode provides structural basis for targeting the unique PDGFR-β promoter G-quadruplex by small molecules and suggests an intriguing strategy of designing drug-like, guanine-conjugated molecules to selectively silence the PDGFR-β gene. Because vG4 formation and dGMP fill-in is a unique property of the PDGFR-β promoter G-quadruplex, our study provides a structural basis for rationally designing small molecule drugs to specifically target the PDGFR-β promoter G-quadruplex to inhibit oncogenic PDGFR-β for cancer therapeutics. Citation Format: Kai-Bo Wang, Jonathan Dickerhoff, Yichen Han, Danzhou Yang. Berberine recognition of the dGMP-bound PDGFR-β promoter G-quadruplex: Structural insight into specific drug targeting. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3842.