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Targeting PDGFR-b promoter vacancy G-quadruplex to suppress gene expression

Award Number: R01CA296831
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Targeting PDGFR-b promoter vacancy G-quadruplex to suppress gene expression - PROJECT SUMMARY Targeting PDGFR-β promoter vacancy G-quadruplex to suppress gene expression Overexpression of platelet-derived growth factor receptor β (PDGFR-β) is an important factor in human cancers and inflammatory diseases. The PDGFR-β signaling pathway is a validated therapeutic target for cancer treatment. Protein kinase inhibitors targeting PDGFR-β have been evaluated in clinical trials, however, they lack specificity and are ineffective against PDGFR-β mutants. G-quadruplex is a globular DNA secondary structure and a new class of molecular targets for anticancer drugs. The human PDGFR-β promoter has a G-quadruplex- forming region that functions as a transcriptional silencer and is targetable by small molecules. The PDGFR-β promoter G-quadruplexes differ significantly from the canonical G-quadruplexes with three complete G-tetrads, such as those formed in MYC and VEGF promoter systems. In contrast, we found that the G-quadruplex formed in the PDGFR-β promoter adopts a unique broken-strand structure which readily forms a vacancy G-quadruplex (vG4) with an incomplete G-tetrad that can be filled-in by an external guanine derivative. Furthermore, we showed that the guanine-fill-in-vG4 can be stabilized by the medicinal natural product berberine and we determined their ternary complex structure by NMR. Significantly, our structure indicates that the unique PDGFR- β vG4 present a specific recognition site for a berberine-guanine conjugate with a berberine linked with a guanine moiety. Therefore, we hypothesize that the unique vG4 formed in the PDGFR-β promoter can be selectively targeted by berberine-guanine conjugates over canonical G-quadruplexes to suppress PDGFR-β transcription in cancer cells. Excitingly, based on our determined NMR structure, we have successfully synthesized two berberine-guanine conjugates that bind the PDGFR-β vG4 with high-affinity and specificity using the G-fill-in recognition mode, and can get into cancer cells and lower PDGFR-β levels. The specific aims are: 1) Structural characterization of berberine-guanine conjugates in complex with the PDGFR-β promoter vG4. 2) Design and synthesize berberine-guanine conjugates using structure-based rational approach that specifically recognize the unique PDGFR-β promoter vG4 for effective gene suppression. 3) Determine the effects of berberine-guanine conjugates on PDGFR-β gene expression and activities in PDGFR-β–driven cancers. The expected outcome of this work is a structure-based rational design and development of novel berberine-guanine conjugates that specifically recognize the unique PDGFR-β promoter vG4 and supress PDGFR-β gene expression. The long- term goal of this proposal is to develop lead compounds of berberine-guanine conjugates for future preclinical testing. The results will have an important positive impact because they lay the groundwork to develop novel guanine conjugates for specific targeting of the PDGFR- silencer element. Further, the targeting compounds developed can serve as molecular probes to investigate protein interactions of the unique PDGFR-β promoter vG4 and provide mechanistic understanding of PDGFR-β gene transcriptional regulation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $2,906,409 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	1	8/18/2025	NEW	$2,906,409
														Subtotal = $2,906,409

Grand Total All Awards = $2,906,409

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Targeting PDGFR-b promoter vacancy G-quadruplex to suppress gene expression

Award Number: R01CA296831

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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