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Crystal structure-based comparison of two NAMPT inhibitors
Sai-Long Zhang1, Tian-Ying Xu1, Zhen-Lin Yang2
1Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
Acta Pharmacologica Sinica
|September 1, 2017
Summary
FK866 shows superior anticancer activity compared to novel NAMPT inhibitor MS0, due to distinct binding modes. This research aids in developing more effective NAMPT inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Nicotinamide phosphoribosyltransferase (NAMPT) inhibition is a promising cancer therapy strategy.
- FK866 and CHS828 are the only NAMPT inhibitors in clinical trials.
- Understanding inhibitor binding modes is crucial for drug development.
Purpose of the Study:
- Compare the biological activity and molecular binding of novel NAMPT inhibitor MS0 with FK866.
- Elucidate the structural basis for differences in their efficacy.
- Inform future chemical optimization of NAMPT inhibitors.
Main Methods:
- Enzyme inhibition assays to determine IC50 values for recombinant human NAMPT.
- Antiproliferation assays in six human cancer cell lines.
- Co-crystal structure determination of human NAMPT complexed with MS0 and FK866.
Main Results:
- FK866 demonstrated significantly lower IC50 values than MS0 for NAMPT inhibition (1.60±0.32 nmol/L vs 9.08±0.90 nmol/L).
- FK866 exhibited superior antiproliferation activity across six cancer cell lines compared to MS0.
- Crystal structures revealed distinct binding interactions: MS0 did not interact with Ser241, while FK866 formed hydrophobic interactions with Arg349.
Conclusions:
- FK866's potent activity is attributed to its specific interactions within the NAMPT active site, differing from MS0.
- The structural insights explain MS0's lower antiproliferative efficacy.
- This study enhances understanding of NAMPT inhibitor mechanisms and guides future anticancer drug design.
