4rlo › Citations

Development of organometallic S6K1 inhibitors.

Qin J, Rajaratnam R, Feng L, Salami J, Barber-Rotenberg JS, Domsic J, Reyes-Uribe P, Liu H, Dang W, Berger SL, Villanueva J, Meggers E, Marmorstein R
J Med Chem 58 305-14 (2015)
Cited: 9 times
EuropePMC logo PMID: 25356520

Abstract

Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.

Reviews - 4rlo mentioned but not cited (1)

  1. Overcoming differences: The catalytic mechanism of metallo-β-lactamases. Meini MR, Llarrull LI, Vila AJ. FEBS Lett 589 3419-3432 (2015)

Articles - 4rlo mentioned but not cited (1)

  1. Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors. Burggraaff L, Lenselink EB, Jespers W, van Engelen J, Bongers BJ, González MG, Liu R, Hoos HH, van Vlijmen HWT, IJzerman AP, van Westen GJP. J Chem Inf Model 60 4283-4295 (2020)


Reviews citing this publication (3)

  1. The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. Zeng L, Gupta P, Chen Y, Wang E, Ji L, Chao H, Chen ZS. Chem Soc Rev 46 5771-5804 (2017)
  2. Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects. Cai H, Dong LQ, Liu F. Trends Pharmacol Sci 37 303-317 (2016)
  3. Beyond controlling cell size: functional analyses of S6K in tumorigenesis. Wu X, Xie W, Xie W, Wei W, Guo J. Cell Death Dis 13 646 (2022)

Articles citing this publication (4)

  1. Organometallic small molecule kinase inhibitors - direct incorporation of Re and 99mTc into Opaganib®. Lengacher R, Wang Y, Braband H, Blacque O, Gasser G, Alberto R. Chem Commun (Camb) 57 13349-13352 (2021)
  2. Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors. Yin Y, Sun Y, Zhao L, Pan J, Feng Y. RSC Med Chem 11 583-590 (2020)
  3. Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2). Gerstenecker S, Haarer L, Schröder M, Kudolo M, Schwalm MP, Wydra V, Serafim RAM, Chaikuad A, Knapp S, Laufer S, Gehringer M. Cancers (Basel) 13 5133 (2021)
  4. Multifunctional Cyclopentadienes as a Scaffold for Combinatorial Bioorganometallics in [(η5 -C5 H2 R1 R2 R3 )M(CO)3 ] (M=Re, 99m Tc) Piano-Stool Complexes. Frei A, Spingler B, Alberto R. Chemistry 24 10156-10164 (2018)


Quick links