Note for: The Unusual Case of Porcupine
Note: The Unusual Case of Porcupine
(doi:10.1126/science.1228179)
Forward chemical genetics:
Know the target of the chemical compound -- screening for the phenotype in cells
Reverse chemical genetics:
Know the protein target -- screening for the action of the chemical compound
The activity dependence of three major signaling molecules on fatty acyl adducts suggests that coordination of cellular behavior in metazoans may be directly influenced by metabolic status of ligand-producing cells.
In light of these challenges and the presumed lack of utility of Porcn inhibitors in the cancer type most strongly linked to Wnt signaling (colorectal cancer), the clinical testing of LGK974 represents a bold move but also reflects a confidence in the ultimate utility of achieving chemical control of key cell fate determination pathways in the management of disease.
The Tnks inhibitors were identified by targeted disruption of the Wnt pathway in colorectal cancer cells that typically carry a mutation in the adenomatous polyposis coli (APC) gene. Such cells harbor an activated Wnt pathway in the absence of Wnt. By contrast, the Porcn inhibitors were identified through a reverse chemical genetics campaign wherein the discovery of compounds precedes their evaluation for therapeutic utility in different disease settings.
The presence of loss-of-function mutations in the LKB1 tumor suppressor kinase gene that restrains the activity of Wnt receptors (Frizzled) and in the RNF43 transmembrane ubiquitin
ligase gene that promotes the turnover of these receptors. Loss of either gene increases Wnt ligand-dependent signaling, which can be reversed by Porcn inhibitors. Given that mutations in RNF43 and LKB1 are frequently observed in cystic pancreatic and lung cancer.
Thus, a need emerges to improve upon reverse chemical genetic strategies for matching disease
to small molecules that increasingly originate from efforts to net chemical probes for basic research rather than for targeting specific genetic mutations.
(doi:10.1126/science.1228179)
Forward chemical genetics:
Know the target of the chemical compound -- screening for the phenotype in cells
Reverse chemical genetics:
Know the protein target -- screening for the action of the chemical compound
Wnt proteins is pivotal in animal development and tissue homeostasis, and has become a high-priority anticancer drug target given its essential role in colorectal cancer and its contribution to a broad range of other cancer types.
Roel Nusse, Varmus linked deviant activity of Wnt molecules to cancer.
LGK974—an acyltransferase called Porcupine (Porcn) that adds fatty acid to Wnt—has been well studied, few of the meeting participants were aware of the drug candidate.
Discovered in screens for genes that affect embryonic patterning in the fruit fly, PORCN is the founding member of a 16-gene family with predicted acyltransferase activity.
The fatty acyl modification of Wnt, Hedgehog, and ghrelin is essential to their activity.
Thus, in the absence of Porcn to catalyze this modification, Wnt proteins remain trapped inside
the cell. This modification is also essential for Wnt binding to their cognate receptors (Frizzled proteins).
In light of these challenges and the presumed lack of utility of Porcn inhibitors in the cancer type most strongly linked to Wnt signaling (colorectal cancer), the clinical testing of LGK974 represents a bold move but also reflects a confidence in the ultimate utility of achieving chemical control of key cell fate determination pathways in the management of disease.
The Tnks inhibitors were identified by targeted disruption of the Wnt pathway in colorectal cancer cells that typically carry a mutation in the adenomatous polyposis coli (APC) gene. Such cells harbor an activated Wnt pathway in the absence of Wnt. By contrast, the Porcn inhibitors were identified through a reverse chemical genetics campaign wherein the discovery of compounds precedes their evaluation for therapeutic utility in different disease settings.
The presence of loss-of-function mutations in the LKB1 tumor suppressor kinase gene that restrains the activity of Wnt receptors (Frizzled) and in the RNF43 transmembrane ubiquitin
ligase gene that promotes the turnover of these receptors. Loss of either gene increases Wnt ligand-dependent signaling, which can be reversed by Porcn inhibitors. Given that mutations in RNF43 and LKB1 are frequently observed in cystic pancreatic and lung cancer.
Thus, a need emerges to improve upon reverse chemical genetic strategies for matching disease
to small molecules that increasingly originate from efforts to net chemical probes for basic research rather than for targeting specific genetic mutations.
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