Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity
| العنوان: | Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity |
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| المؤلفون: | Ashutosh S. Jogalekar, Mellem Kevin, Chris M. Semko, Andreas Buckl, Elena S. Koltun, Jacqueline Smith, Naing Aay, Mallika Singh, Christos Tzitzilonis, Robert J. Nichols, Won Walter, Nidhi Tibrewal, Zhengping Wang, Kasia Mordec, Adrian Liam Gill, Gert Kiss, Abby Marquez, Susan E. Wilson, Mae Saldajeno-Concar, David Wilds |
| المصدر: | Cancer Research. 78:4878-4878 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Scaffold protein, 030103 biophysics, Cancer Research, Kinase, Chemistry, Allosteric regulation, Phosphatase, Protein tyrosine phosphatase, Pharmacology, 03 medical and health sciences, Oncology, Signal transduction, Receptor, ADME |
| الوصف: | Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS and its downstream effectors. Guided by structural insights from X-ray data, we describe a strategy aimed at the identification of a highly potent and selective allosteric SHP2 inhibitor series. Our efforts led to the discovery of RMC-4550, a potent and selective SHP2 inhibitor which exhibits a high quality, drug-like preclinical profile. RMC-4550 inhibits purified, activated full length human SHP2 with an IC50 of 1.55 nM, and has cellular IC50 of 39 nM in PC9 cells with a pERK readout. RMC-4550 has no detectable inhibitory activity up to 10 µM against the catalytic domain of SHP2, a panel of 14 additional protein phosphatases, and a panel of 468 protein kinases. RMC-4550 exhibits low to moderate cross species in vitro intrinsic clearance (3.6-24 µL/min/million cells) in hepatocytes, a high passive permeability (458 nm/s) and efflux ratio of 1. The ADME properties translate into favorable pharmacokinetic profiles in preclinical species. RMC-4550 has moderate to high bioavailability and has a half-life amenable for once daily oral administration. In the EGFR-driven KYSE-520 human esophageal cancer xenograft model, we observed a dose dependent efficacy consistent with target modulation, assessed by phospho-ERK inhibition in tumors. RMC-4550 is well tolerated at doses that achieved maximal and sustained efficacy in this model. RMC-4550 was synthesized in 5 linear (6 total) steps from the readily accessible or commercially available intermediates. The chemical structure and synthesis of RMC-4550, along with detailed structure-activity relationships will be presented. In summary, RMC-4550 exemplifies a novel class of potent allosteric inhibitors of SHP2 with an excellent drug like property profile. Citation Format: Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar, Gert Kiss, Abby Marquez, Kevin T. Mellem, Kasia Mordec, Mae Saldajeno-Concar, Chris M. Semko, Nidhi Tibrewal, Christos Tzitzilonis, Walter Won, Jacqueline A. Smith, Susan E. Wilson, Robert J. Nichols, Zhengping Wang, David Wilds, Mallika Singh, Adrian L. Gill. RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4878. |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2018-4878 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::b9799dbbd6e549ae1405a9baa4fbc959 https://doi.org/10.1158/1538-7445.am2018-4878 |
| رقم الانضمام: | edsair.doi...........b9799dbbd6e549ae1405a9baa4fbc959 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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| DOI: | 10.1158/1538-7445.am2018-4878 |