SERP
Comments:
HAMI3379 is a compound that antagonizes cysteinyl leukotriene 2 (CysLT2) receptor without affecting a closely related cysteinyl leukotriene 1 (CysLT1) receptor when used at concentrations < 100 nM. The compound suggested as orthogonal probe, zafirlukast, should be used to rule out effects via CysLT1, as zafirlukast seems to be highly selective for CysLT1 over CysLT2. So, using these two compounds may offer an opportunity to distinguish CysLT2 vs. CysLT1 biology. It should be noted that the two receptors are closely related and that developing antagonists selective for one over the other has been challenging (I recommend the following reference for structure-based analysis of the receptors bound to dual targeting antagonists which helps illuminate some of these issues: 10.1038/s41467-019-13348-2).
However, it is also important to note that HAMI3379 has not been widely profiled against additional G-protein coupled receptors (GPCRs). This could be a problem as one of the orphan GPCRs, GPR17, was reported as a target for HAMI3379 (DOI: 10.1016/j.chembiol.2018.03.012). Given the structural similarity between GPCRs, there might be other GPCRs that are antagonized by HAMI3379, and this remains to be tested. Therefore, when using HAMI3379 to probe CysLT2 it is critical that the compound is not used above the recommended concentration of < 100 nM. For example, effects on GPR17 seem to require ~10 uM HAMI3379.
In conclusion, HAMI3379 is a good probe for studying what happens when CysLT2 activity is antagonized, provided the compound is used at less than 100 nM concentrations. Any studies done at concentrations exceeding 10 µM of HAMI3379 can't be interpreted as due to CysLT2, as at those high concentrations this compound affects GPR17 and probably CysLT1 as well.
(last updated:
6 Dec 2022 )
