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Developing Quinoline-based Secretagogues for Prostate Apoptosis Response-4 Protein (Par-4) as Potential Antineoplastic Agents

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Tumor Suppressor Par-4

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Abstract

Secretagogues bearing a 3-arylquinoline scaffold-induced secretory events in normal cells that released the tumor suppressor protein, prostate apoptosis response-4 protein (Par-4) sequestered by the intermediary filament protein, vimentin. The secretion of the Par-4 protein and its binding to a selective, cell-surface receptor GRP78 subsequently triggered paracrine apoptosis in cancer cells. These findings provided a rationale for the study of Par-4 secretagogues as potential agents for the inhibition of tumor growth. Developing secretagogues with these scaffolds, determining vimentin as the biomolecular target, using molecular dynamics to model arylquin binding to vimentin, and understanding the secretion of Par-4 and its apoptotic effects held promise as a new approach for small-molecule interventions as potential treatments for cancer.

Vitaliy M. Sviripa and Ravshan Burikhanov shared equally in the development of this work.

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Abbreviations

Aq-1 or Arylquin-1:

3-(2-Fluorophenyl)-N7,N7-dimethylquinoline-2,7-diamine

BFA:

brefeldin A

CM:

cell-culture conditioned medium

CQ:

chloroquine

CYP:

cytochrome P450 monooxygenases

DMF:

Dimethylformamide

EDC:

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

EMT:

Epithelial to Mesenchymal transition

ERES:

Exit-site-from-the-endoplasmic-reticulum

ERGIC:

Endoplasmic Reticulum-to-Golgi Intermediate Compartment

ER:

Endoplasmic reticulum

Et3N:

Triethylamine

FIDAS agents:

(E)-4-(2,6-Difluorostyryl)-N,N-dimethylanilines

GDP:

guanosine diphosphate

GRP78:

Glucose-regulated protein-78

GTP:

guanosine triphosphate

HOBt:

1-Hydroxybenzotriazole hydrate

LMP:

lysosomal membrane permeabilization

MAT-2:

methionine S-adenosyltransferase-2

MDM2:

minute-double-minute-2 protein, an E3 ligase

NSAID:

non-steroidal anti-inflammatory drug

Nutlin-3a:

4-[(4S,5R)-4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one

Par-4:

Prostate Apoptosis Response-4 Protein

PEG:

polyethylene glycol spacer (CH2CH2O)n

SAC:

Selective-for-Apoptosis-Induction-Cancer domain [104, 105]

SAR:

Structure–activity relationships

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Acknowledgments

CL and DSW were supported by NIH R01 CA172379 from the National Institutes of Health, the Lucille Parker Markey Cancer Center at the University of Kentucky, and by NIH UL1 TR000117 from the National Institutes of Health to the University of Kentucky’s Center for Clinical and Translational Science. DSW was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, NIH P30 RR020171 from the National Institute of General Medical Sciences to L. Hersh; and NIH R01 CA60872 from the National Cancer Institute to Vivek M. Rangnekar. We thank Ms. Elise Wright in the Markey Cancer Center for her artistry in constructing Fig. 1.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA

    Vitaliy M. Sviripa

  2. Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA

    Ravshan Burikhanov

  3. Department of Molecular and Cellular Biochemistry, Lucille Parker Markey Cancer Center, College of Medicine, Lexington, KY, USA

    Chunming Liu & David S. Watt

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  1. Vitaliy M. Sviripa
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  4. David S. Watt
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Correspondence to David S. Watt .

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  1. Assoc Dir, Markey Cancer Center, Univ of Kentucky, Lexington, KY, USA

    Vivek M. Rangnekar

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David S. Watt and Chunming Liu hold an equity interest in a for-profit corporation, Epionc, Inc., founded for the purpose of advancing translational research involving antineoplastic agents. The co-inventors have complied with the University’s policies regarding intellectual property disclosure and conflict of interest issues. The University of Kentucky has filed patent applications for compounds for which these authors are co-inventors.

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Sviripa, V.M., Burikhanov, R., Liu, C., Watt, D.S. (2021). Developing Quinoline-based Secretagogues for Prostate Apoptosis Response-4 Protein (Par-4) as Potential Antineoplastic Agents. In: Rangnekar, V.M. (eds) Tumor Suppressor Par-4. Springer, Cham. https://doi.org/10.1007/978-3-030-80558-6_11

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