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. 2017 Nov 30;5(1):e1395504.
doi: 10.1080/23723556.2017.1395504. eCollection 2018.

Dimeric quinacrines as chemical tools to identify PPT1, a new regulator of autophagy in cancer cells

Michael C Nicastri  1 , Vito W Rebecca  2 , Ravi K Amaravadi  2   3 , Jeffrey D Winkler  1   3
Affiliations

Dimeric quinacrines as chemical tools to identify PPT1, a new regulator of autophagy in cancer cells

Michael C Nicastri et al. Mol Cell Oncol. .

Abstract

DQ661 is a novel dimeric quinacrine that affects multiple lysosomal functions (autophagy and macropinocytosis) and mTORC1 (mechanistic target of rapamycin) activity by specifically targeting protein-palmitoyl thioesterase 1 (PPT1). DQ661 has in vivo activity in immunocompetent mouse models of cancer, and constitutes a new tool compound for the study of lysosomal function in cancer and therapeutic resistance.

Keywords: PPT1; autophagy; lysosome; mTOR; macropinocytosis.

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Figures

Figure 1.
Figure 1.
Schematic summary of the invention of DQ661 (a dimeric quinacrine autophagy/lysosome inhibitor), the identification of Protein Palmitoyl Thioesterase 1 (PPT1), and their influence on lysosomal biology. A) Depicts the chemical strategy in the design and synthesis of lysosomal inhibitor DQ661. Newly described compounds are abbreviated with the identity of their parent heterocycle: dimeric chloroquine (DC), dimeric quinacrine (DQ), dimeric primaquine (DP), and dimeric mefloquine (DM). After the two letter code, the length of the polyamine linker is specified by the first two numbers, and followed by a zero (Unmethylated) or one (methylated) B) Outline of a photoaffinity experiment which identifies PPT1 as a protein binding partner of DQ661 C) Schematic demonstrating how DQ661-mediated inhibition of PPT1 results in the disruption of physical interaction of key protein complexes involved in lysosomal acidification and mTORC1 (mechanistic target of rapamycin) activation.
See this image and copyright information in PMC

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