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SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF ALLOSTERIC INHIBITORS OF THE AAA ATPASE P97

Alverez, Celeste (2019) SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF ALLOSTERIC INHIBITORS OF THE AAA ATPASE P97. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

This thesis describes the design and synthesis of allosteric, small molecule inhibitors targeting
the cancer relevant p97. Due to its pivotal role of maintaining proteostasis, while both normal
and cancerous cells need p97, cancerous cells become reliant on its activity to survive. Based on
the initial success of proteosome inhibitors it was proposed that targeting p97, which functions
upstream of the proteosome, will mitigate compensatory pathway activation observed with
proteosome inhibition. In order to test this hypothesis, a campaign to identify small molecule
inhibitors of p97 was initiated which identified three distinct chemotypes: two related
chemotypes contained indole cores that were initially explored, and a third alkylsulfanyl-1,2,4-
triazole based molecule that was found to be the most amenable to modification. The best
compound reported in the initial publication, NMS-873, was shown to possess good potency, but
poor solubility. Therefore, modification of this chemotype focused on incorporating solubilizing
groups and reducing lipophilicity of the linear side chain of the molecule including various
carbamate containing aliphatic heterocycles. Additional changes focused on improving potency
while considering stability. To accomplish this, the thioether was replaced with an ether linker or
oxidizing it to a sulfone. In addition, difluorination of the phenol side chain to reduce electron
density of the ring was found to significantly improve potency. Through an iterative structureactivity
relationship effort, five analogs with unique structural features were identified that
maintained or improved activity relative to NMS-873.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Alverez, Celesteceleste.alverez@gmail.comcea28
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.edupwipf0000-0001-7693-5863
Committee MemberGold, Barrygoldbi@pitt.edugoldbi0000-0002-2610-978X
Committee MemberHorne, W. Sethhorne@pitt.eduhorne0000-0003-2927-1739
Committee MemberHuryn, Donnahuryn@pitt.eduhuryn0000-0001-5542-4968
Date: 9 December 2019
Date Type: Publication
Defense Date: 21 November 2019
Approval Date: 9 December 2019
Submission Date: 6 December 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 563
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: medicinal chemistry
Date Deposited: 09 Dec 2019 14:14
Last Modified: 09 Dec 2019 14:14
URI: http://d-scholarship.pitt.edu/id/eprint/37936

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