Alverez, Celeste
(2019)
SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF ALLOSTERIC
INHIBITORS OF THE AAA ATPASE P97.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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Unpublished |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: |
|
| ETD Committee: |
|
| 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 2021 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37936 |
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