L-755507 | CAS:159182-43-1

Biological Activity

L-755507 is a potent partial agonist of β3-adrenergic receptor with an EC50 value of 0.43 nM for cloned human receptors, ^[1] with over 400-fold selectivity for the β3-receptor over β1- and β2- receptors. L-755507 was found to stimulate lipolysis in human adipose tissue ^[2] and promote urinary bladder relaxation. ^[3] It was also found to increase CRISPR-mediated HDR efficiency, but more research is needed to understand its underlying mechanism. 

L-755,507 is also known as a selective β3-adrenergic receptor partial agonist.
Target (In vitro) IC50 (nM) ^[1]
(cloned human) β3-adrenergic receptor 13 +/- 7.2

Successful Applications in CRISPR

(i) L-755507 enhanced CRISPR-mediated HDR efficiency in mouse E14 embryonic stem cells (ESCs) by 3-fold for large fragment insertions (via a circular template plasmid) and 9-fold for point mutations [via single-stranded oligodeoxy-nucleotide (ss-ODN)] in human induced pluripotent stem cells (iPSCs). Maximal effects were achieved with 5 μM of L755507. ^[4]
(ii) L-755507 was tested in a variety of cell types [K562, HeLa, primary neonatal cells (human umbilical vein endothelial cell (HUVEC) and fibroblast CRL-2097), and human ESC-derived cells], targeting the ACTA2 locus, for which an improved HDR efficiency was consistently observed. The largest increase of more than 2- fold was obtained for HUVECs.^[4]
(iii) Li and colleagues found that L755507 increased the expression of several CRISPR/Cas9-mediated HDR associated genes including RAD51 in porcine fetal fibroblasts. Moreover, it decreased the expression of several NHEJ repair-related genes. Results from an eGFP reporter assay demonstrated that HDR efficiency was increased by approximately 2-fold. Maximal effects were achieved with 40 μM L755507. ^[5]
(iv) The effect of L755507 on HDR-mediated (large fragment) knock-in was also examined in primary porcine cell lines. L755507 was able to generate up to 51.61% CRISPR/Cas9-mediated knock-in cell lines, whereas control cells treated with DMSO only generated 26.22 %. ^[5]

Reference:

1. Fisher, M. H., Amend, A. M., Bach, T. J., Barker, J. M., Brady, E. J., Candelore, M. R., Carroll, D., Cascieri, M. A., Chiu, S. H., Deng, L., Forrest, M. J., Hegarty-Friscino, B., Guan, X. M., Hom, G. J., Hutchins, J. E., Kelly, L. J., Mathvink, R. J., Metzger, J. M., Miller, R. R., Ok, H. O., … MacIntyre, D. E. (1998). A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. The Journal of clinical investigation, 101(11), 2387–2393. https://doi.org/10.1172/JCI2496
2. Umekawa, T., Yoshida, T., Sakane, N., Kogure, A., Kondo, M., & Honjyo, H. (1999). Trp64Arg mutation of beta3-adrenoceptor gene deteriorates lipolysis induced by beta3-adrenoceptor agonist in human omental adipocytes. Diabetes, 48(1), 117–120. https://doi.org/10.2337/diabetes.48.1.117
3. Nomiya, M., & Yamaguchi, O. (2003). A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor suptypes and their functional roles in human normal and obstructed bladders. The Journal of urology, 170(2 Pt 1), 649–653. https://doi.org/10.1097/01.ju.0000067621.62736.7c
4. Yu, C., Liu, Y., Ma, T., Liu, K., Xu, S., Zhang, Y., Liu, H., La Russa, M., Xie, M., Ding, S., & Qi, L. S. (2015). Small molecules enhance CRISPR genome editing in pluripotent stem cells. Cell stem cell, 16(2), 142–147. https://doi.org/10.1016/j.stem.2015.01.003
5. Li, G., Zhang, X., Zhong, C., Mo, J., Quan, R., Yang, J., Liu, D., Li, Z., Yang, H., & Wu, Z. (2017). Small molecules enhance CRISPR/Cas9-mediated homology-directed genome editing in primary cells. Scientific reports, 7(1), 8943. https://doi.org/10.1038/s41598-017-09306-x

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