Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma.
ER stress
ERMM
IRMM
UPR
protein disulfide isomerase PDIA1
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
28 May 2021
28 May 2021
Historique:
received:
27
04
2021
revised:
19
05
2021
accepted:
22
05
2021
entrez:
2
6
2021
pubmed:
3
6
2021
medline:
3
6
2021
Statut:
epublish
Résumé
Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34
Identifiants
pubmed: 34071205
pii: cancers13112649
doi: 10.3390/cancers13112649
pmc: PMC8198550
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Velosano
ID : pilot award
Organisme : cleveland clinic foundation
ID : start-up fund
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