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Investigating the Interaction of a Selective Peptoid Probe and Rpn-13, A Non-Essential Ubiquitin Receptor of the Proteasome

Award Number: F31CA247327
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/13/2020
PERIOD OF PERFORMANCE END DATE: 02/12/2023

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Investigating the Interaction of a Selective Peptoid Probe and Rpn-13, A Non-Essential Ubiquitin Receptor of the Proteasome - PROJECT SUMMARY Targeting the ubiquitin-proteasome system has greatly contributed to the treatment of hematological cancers over the past fifteen years. Despite the success of these proteasome-targeted drugs (such as bortezomib, Btz) that inhibit the proteasome’s catalytic function, eventual drug resistance and off-target toxicities demand for alternative therapies to treat patients that become resistant to current treatments or for refractory cases. To overcome the current challenges, many groups have begun targeting the regulatory subunits of the proteasome. Rpn-13, a ubiquitin receptor on the proteasome’s regulatory particle, has been one of the most promising targets as it is not an essential proteasome subunit in healthy cells. Our central hypothesis is that inhibition of the proteasome’s regulatory function, specifically the Rpn-13 subunit, can overcome Btz-resistant mechanisms, working as an alternative therapy for multiple myeloma (MM) patients. With current inhibitors RA190 and KDT-11, Rpn-13 inhibition is observed to be toxic to MM in in vitro and in vivo applications. Since KDT-11 has been shown to be more selective than RA190, the long-term goal of this research project is to develop Rpn-13 inhibitors with improved potency and physical properties that bind to the same surface as KDT- 11 and maintain KDT-11’s selectively. The objective for this application is to utilize KDT-11 as a chemical probe to characterize and to explore its mechanism of action with Rpn-13 and in MM cell lines. To complete this objective, we propose the following specific aims: (1) To determine the binding site of the peptoid probe KDT-11 on Rpn-13, and (2) to evaluate KDT-11’s effect on Rpn-13 and apoptotic pathways in MM and Btz-resistant MM. Peptoids, such as KDT-11, have been considered potential therapeutic agents but previously reported peptoid probes have not been further investigated or optimized either due to low-affinity or non-selectivity. This proposal is innovative, in our opinion, because we plan to transition a selective peptoid probe with modest affinity to a more lead-like scaffold to develop more potent and pharmacologically-amenable Rpn-13 inhibitors. This contribution is expected to be significant because the discovery of KDT-11’s binding site and the evaluation of its mechanism of action in Btz-resistant MM would allow for optimization of the only reported reversible selective inhibitor for Rpn-13, which would lead to a greater understanding for alternative targets for MM treatment.


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: 2024 ( Subtotal = -$18,711 )
2024	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	3	12/28/2023	NON-COMPETING CONTINUATION	-$18,711
														Subtotal = -$18,711

Issue Date FY: 2022 ( Subtotal = $32,026 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	3	7/25/2022	NON-COMPETING CONTINUATION	$32,026
														Subtotal = $32,026

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Research Manpower	000	2	6/24/2021	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $46,036

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Research Manpower	000	1	6/29/2020	NEW	$45,520
														Subtotal = $45,520

Grand Total All Awards = $104,871

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Investigating the Interaction of a Selective Peptoid Probe and Rpn-13, A Non-Essential Ubiquitin Receptor of the Proteasome

Award Number: F31CA247327

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/13/2020

PERIOD OF PERFORMANCE END DATE: 02/12/2023

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