Tuesday, July 1, 2025 7/1/2025

Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines

Award Number: R01CA177585
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2026

Group Awards By:

View Award Description

Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines - PROJECT SUMMARY Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines G-quadruplex (G4) DNA is a globular DNA secondary structure and considered as a new class of molecular targets for anticancer drugs. MYC, one of the most commonly deregulated genes in human cancers, has a DNA G4 motif in its promoter that functions as a transcriptional silencer. Compounds that bind to and stabilize the G-quadruplex formed in the MYC promoter have been shown to significantly lower MYC levels in cancer cells. Thus, the MYC promoter G-quadruplex (MycG4) represents a novel target for MYC inhibition by small molecules. However, little is known about how MycG4 is regulated by proteins and development of MycG4- targeting drugs has been focused solely on G4 DNA. Whereas drug-DNA interactions may be insufficient for MYC inhibition, the effective mechanism of drug action could involve protein-DNA interactions, which is analogous to topoisomerase inhibitors. Very recently, we have discovered that indenoisoquinolines, a clinically tested scaffold with excellent drug-like properties, are strong MycG4 binders and potent MYC inhibitors. We have also discovered that the DDX5 helicase actively unfolds MycG4 and is critically involved in MYC gene transcriptional activation. These results provide new and critical insights to effectively downregulate MYC transcription by targeting MycG4 and its interactions with DDX5. Our central hypothesis is that indenoisoquinolines effectively suppress MYC transcription by binding to the MYC promoter G-quadruplex and disrupting DDX5-MycG4 interactions. The overall objective is to determine the molecular mechanism of effective MYC inhibition by indenoisoquinolines, establish the structure–activity relationships (SAR), and discover lead indenoisoquinolines for preclinical testing. The long-term research goal is to develop potent indenoisoquinoline MYC inhibitors as new anticancer drugs. The specific aims are: 1) Structural characterization of the MycG4-indenoisoquinoline complexes. 2) Establishing a compound library to determine indenoisoquinolines that bind MycG4 and inhibit MYC. 3) Determining the effect of MycG4-interactive indenoisoquinolines on DDX5 unfolding of the MYC promoter G4 and how this correlates with MYC suppression. 4) Designing and synthesizing optimized indenoisoquinolines for MYC suppression using structure-based rational approach; establishing SAR for MycG4-binding and inhibition of DDX5 unfolding. The expected outcome of this work is a determination of the SAR of indenoisoquinolines for MycG4-targeting, demonstration of the effective MYC suppression by inhibiting DDX5-MycG4 interaction, and discovery of lead compounds for future preclinical testing. The results will have an important positive impact because they lay the groundwork to develop new indenoisoquinoline anticancer drugs with MYC-targeted activity.


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 = $387,242 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	10	6/16/2025	NON-COMPETING CONTINUATION	$387,242
														Subtotal = $387,242

Issue Date FY: 2024 ( Subtotal = $367,880 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	9	6/11/2024	NON-COMPETING CONTINUATION	$367,880
														Subtotal = $367,880

Issue Date FY: 2023 ( Subtotal = $381,381 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	8	5/22/2023	NON-COMPETING CONTINUATION	$381,381
														Subtotal = $381,381

Issue Date FY: 2022 ( Subtotal = $385,297 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	001	7	5/25/2022	NON-COMPETING CONTINUATION	$385,297
2022	2018	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Cause and Prevention Research	000	5	10/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $385,297

Issue Date FY: 2021 ( Subtotal = $393,161 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Biology Research	001	6	1/28/2021	COMPETING CONTINUATION	$393,161
2021	2018	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Cause and Prevention Research	000	5	1/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $393,161

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Cause and Prevention Research	000	5	7/15/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $533,792 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Biology Research	001	5	9/18/2018	SUPPLEMENT FOR EXPANSION	$150,270
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Cause and Prevention Research	000	5	6/15/2018	NON-COMPETING CONTINUATION	$383,522
														Subtotal = $533,792

Issue Date FY: 2017 ( Subtotal = $383,638 )
2017	2017	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Cause and Prevention Research	000	4	6/20/2017	NON-COMPETING CONTINUATION	$383,638
														Subtotal = $383,638

Issue Date FY: 2016 ( Subtotal = $383,638 )
2016	2016	PURDUE UNIVERSITY	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Cause and Prevention Research	001	3	7/5/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$383,638
2016	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cancer Cause and Prevention Research	000	2	7/5/2016	NON-COMPETING CONTINUATION	-$149,886
2016	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cancer Cause and Prevention Research	002	2	8/25/2016	NON-COMPETING CONTINUATION	$149,886
														Subtotal = $383,638

Issue Date FY: 2015 ( Subtotal = $369,569 )
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cancer Cause and Prevention Research	000	2	5/7/2015	NON-COMPETING CONTINUATION	$369,569
														Subtotal = $369,569

Issue Date FY: 2014 ( Subtotal = $369,569 )
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cancer Cause and Prevention Research	000	1	5/21/2014	NEW	$369,569
														Subtotal = $369,569

Grand Total All Awards = $3,955,167

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines

Award Number: R01CA177585

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer