TY - JOUR
T1 - Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network
AU - Skácel, Jan
AU - Slusher, Barbara S.
AU - Tsukamoto, Takashi
N1 - Funding Information:
The authors of this manuscript have been supported by NIH Grants P30MH075673 (B.S.S) and R01AG059799 (B.S.S. and T.T.) and a Tau Pipeline Enabling Program Grant T-PEP-18-579974C jointly funded by the Alzheimer’s Association and Rainwater Charitable Foundation (to B.S.S). The authors are also grateful for the support provided by the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.
Publisher Copyright:
©
PY - 2021/1/14
Y1 - 2021/1/14
N2 - Ceramides are composed of a sphingosine and a single fatty acid connected by an amide linkage. As one of the major classes of biologically active lipids, ceramides and their upstream and downstream metabolites have been implicated in several pathological conditions including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation. Consequently, tremendous efforts have been devoted to deciphering the dynamics of metabolic pathways involved in ceramide biosynthesis. Given that several distinct enzymes can produce ceramide, different enzyme targets have been pursued depending on the underlying disease mechanism. The main objective of this review is to provide a comprehensive overview of small molecule inhibitors reported to date for each of these ceramide-producing enzymes from a medicinal chemistry perspective.
AB - Ceramides are composed of a sphingosine and a single fatty acid connected by an amide linkage. As one of the major classes of biologically active lipids, ceramides and their upstream and downstream metabolites have been implicated in several pathological conditions including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation. Consequently, tremendous efforts have been devoted to deciphering the dynamics of metabolic pathways involved in ceramide biosynthesis. Given that several distinct enzymes can produce ceramide, different enzyme targets have been pursued depending on the underlying disease mechanism. The main objective of this review is to provide a comprehensive overview of small molecule inhibitors reported to date for each of these ceramide-producing enzymes from a medicinal chemistry perspective.
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U2 - 10.1021/acs.jmedchem.0c01664
DO - 10.1021/acs.jmedchem.0c01664
M3 - Review article
C2 - 33395289
AN - SCOPUS:85100069538
SN - 0022-2623
VL - 64
SP - 279
EP - 297
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -