Reference Detail

Ref Type

Journal Article

PMID

(29967249)

Authors

Gu L, Lingeman R, Yakushijin F, Sun E, Cui Q, Chao J, Hu W, Li H, Hickey RJ, Stark JM, Yuan YC, Chen Y, Vonderfecht SL, Synold TW, Shi Y, Reckamp KL, Horne D, Malkas LH

Title

The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	23	2018 12 01	6053-6065	Clin Cancer Res

URL

Abstract Text

Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was ubiquitously expressed in a broad range of cancer cells and tumor tissues, but not significantly in nonmalignant cells. We found the L126-Y133 region of caPCNA is structurally altered and more accessible to protein-protein interaction. A cell-permeable peptide harboring the L126-Y133 sequence blocked PCNA interaction in cancer cells and selectively kills cancer cells and xenograft tumors. On the basis of these findings, we sought small molecules targeting this peptide region as potential broad-spectrum anticancer agents.By computer modeling and medicinal chemistry targeting a surface pocket partly delineated by the L126-Y133 region of PCNA, we identified a potent PCNA inhibitor (AOH1160) and characterized its therapeutic properties and potential toxicity.AOH1160 selectively kills many types of cancer cells at below micromolar concentrations without causing significant toxicity to a broad range of nonmalignant cells. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell-cycle arrest. It induces apoptosis in cancer cells and sensitizes them to cisplatin treatment. AOH1160 is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it does not cause significant toxicity at 2.5 times of an effective dose.These results demonstrated the favorable therapeutic properties and the potential of AOH1160 as a broad-spectrum therapeutic agent for cancer treatment.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AOH1160	AOH1160	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AOH1160				AOH1160 is a small molecule inhibitor that specifically targets cancer associated PCNA (caPCNA) and binds to the region between L126 and Y133, thereby interfering with elongation of the replication fork, and subsequently leading to cell cycle arrest, apoptosis, and tumor growth inhibition (PMID: 29967249).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References