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Design, Synthesis, and Biological Evaluation of Novel p62 Ligands with Therapeutic Effects

Ma, Shifan (2021) Design, Synthesis, and Biological Evaluation of Novel p62 Ligands with Therapeutic Effects. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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p62 is a multifunctional protein containing multiple protein interaction domains, which participate in a wide array of signaling pathways. Among them, p62 is closely involved in autophagy and the ubiquitin-proteasome system (UPS) via its PB1, LIR, and ubiquitin-bounding domain (UBA) motifs. Our lab discovered the first small molecule ligand XRK3 as our lead that interacts with p62 through its ZZ domain. Our previous studies found that XRK3 showed an inhibitory potency on myeloma cell growth and reduced tumor size, and it recovered bone formation in myeloma models. To increase the efficacy and improve the pharmacokinetic profile of XRK3, we performed chemical modification on XRK3 and screened the anti-proliferative effects on three multiple myeloma cell lines. We identified compound 6.28, which has a higher in vitro anti-proliferative effect (IC50 < 500nM). Compound 6.28 also has good in vitro druggable properties and increases autophagosome number without inducing autophagy flux. The mechanism underlying this anti-tumor effect can be illustrated by signaling studies that show procaspase-8 accumulation, which causes procaspase-8 self-activation and activation of apoptosis signaling that results in cell death.
In addition, we found that a majority of our compounds can enhance autophagosome formation as represented by LC3B conversion. If our compounds activate autophagy flux and increase the clearance of misfolded and aggregated proteins in the brain by the autophagic process, they might be helpful in reducing help reduce the neurotoxic proteins that cause some degenerative disorders. This hypothesis is consistent with a previous study by Dr. Kwon, who found thatXRK3 can increase the mutant huntingtin clearance by autophagy. Therefore, we measured the neuroprotective effects of our compounds in differentiated SH-SY5Y cells against hydrogen peroxide, which is associated with oxidative stress and neurotoxicity. We discovered a compound capable of inducing autophagic flux and reducing tau and α-synuclein levels with demonstrated neuroprotective effect. This compound 5.8 may have therapeutic relevance towards the treatment of neurodegenerative diseases.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ma, Shifanshm100@pitt.eduSHM1000000-0001-6292-125X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorXie, Xiang-QunSean.Xie@pitt.eduSean.XIE
Committee CoChairGibbs, Robertgibbsr@pitt.edugibbsr
Committee MemberWang,
Committee MemberFloreancig, Paulflorean@pitt.eduflorean
Committee MemberMcGuire, Terencetfm1@pitt.edutfm1
Committee MemberMcDermott, Leeam179@pitt.eduam179
Date: 13 August 2021
Date Type: Publication
Defense Date: 22 March 2021
Approval Date: 13 August 2021
Submission Date: 11 August 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 616
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: p62/SQSTM1, p62-ZZ ligands, multiple myeloma, neurodegenerative diseases, autophagy, oxidative stress.
Date Deposited: 13 Aug 2021 17:56
Last Modified: 13 Aug 2023 05:15


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