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Development of Stabilized Zampanolide Mimics as Chemotherapeutics for Prostate Cancer

Award Number: SC2GM121185
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Development of Stabilized Zampanolide Mimics as Chemotherapeutics for Prostate Cancer - Project Summary Abstract: Approximately 30,000 American men die each year of metastatic castration-resistant prostate cancer (CRPC) due to the inevitable progression of resistance to first-line treatment with Docetaxel. As a unique addition to the family of microtubule-stabilizing cytotoxic agents (MSAs), zampanolide covalently binds to-tubulin, whereas docetaxel binds non-covalently. This has opened up new avenues to more-effective chemotherapeutics for CRPC. However, limited supply of natural zampanolide from the wild constitutes a serious obstacle to support further drug development activities. Four published synthetic approaches are not efficient and CANNOT serve as its alternative source for further development as a drug candidate. More importantly, we envision that zampanolide possesses poor pharmacokinetic profiles as a drug candidate due to its chemically fragile side chain and metabolically vulnerable lactone moiety. The objective of the proposed research is therefore to develop zampanolide mimics to improve their pharmacokinetic profiles, therapeutic window, and synthetic efficiency yet retain the impressive therapeutic potency and unique mechanism of action for potentially clinical treatment of CRPC. The fundamental hypotheses of this project are: 1) that bioisosteric replacements of the N-acyl hemiaminal side chain and of the lactone in core structure of zampanolide will improve their chemically and metabolically stability yet retain the impressive cytotoxic potency as well as the unique mechanism of action; and 2) remodeling the side chain and/or simplification of the core structure will enable the syntheses to be means for a reliable and renewable source of material. The following specific studies will be carried out to test these hypotheses: 1) To establish stabilized mimics of (-)-zampanolide and practical synthetic methods. A group of zampanolide mimics, with N-acyl hemiaminal and lactone moiety remodeled, will be synthesized by practical and manageable methods. The cytotoxic and anti-proliferative potency against both drug-sensitive and resistance prostate cancer cells will be assessed; 2) To identify simplified and stabilized mimics as well as manageable synthetic methods. A group of new stabilized zampanolide mimics with a simplified core will be synthesized and evaluated; 3) To define the in vitro pharmacokinetic profiles and toxicity of promising mimics; and 4) To validate the covalently-binding mechanism of action as MSAs. This proposal is expected to result in, at least, a new stabilized zampanolide mimic with retained in vitro potency against both drug-sensitive and resistant prostate cancer cells and unique mechanism of action, as well as good in vitro pharmacokinetic and safety profiles. This proposal will bring to my research group with techniques in in vitro pharmacokinetic and mechanistic studies of drug actions and allow me to bring high quality research experiences to the undergraduate and graduate students, and position me to be competitive for SC1, R15, R01, and other NIH awards in the future.


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: 2023 ( Subtotal = -$335 )
2023	2019	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	3	11/10/2022	NON-COMPETING CONTINUATION	-$335
														Subtotal = -$335

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	CALIFORNIA STATE UNIVERSITY, FRESNO	5241 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	3	8/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $140,000 )
2019	2019	CALIFORNIA STATE UNIVERSITY, FRESNO	5241 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	3	8/1/2019	NON-COMPETING CONTINUATION	$140,000
														Subtotal = $140,000

Issue Date FY: 2018 ( Subtotal = $140,000 )
2018	2018	CALIFORNIA STATE UNIVERSITY, FRESNO	5241 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	2	8/16/2018	NON-COMPETING CONTINUATION	$140,000
														Subtotal = $140,000

Issue Date FY: 2017 ( Subtotal = $140,000 )
2017	2017	CALIFORNIA STATE UNIVERSITY, FRESNO	5241 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	1	8/24/2017	NEW	$140,000
														Subtotal = $140,000

Grand Total All Awards = $419,665

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Development of Stabilized Zampanolide Mimics as Chemotherapeutics for Prostate Cancer

Award Number: SC2GM121185

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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