Lategahn, Jonas, Tumbrink, Hannah L., Schultz-Fademrecht, Carsten, Heimsoeth, Alena, Werr, Lisa ORCID: 0000-0002-3697-4136, Niggenaber, Janina, Keul, Marina, Parmaksiz, Fatma ORCID: 0009-0003-3771-7128, Baumann, Matthias, Menninger, Sascha, Zent, Eldar, Landel, Ina, Weisner, Joern, Jeyakumar, Kirujan ORCID: 0000-0002-0184-6775, Heyden, Leonie, Russ, Nicole, Mueller, Fabienne, Lorenz, Carina, Braegelmann, Johannes, Spille, Inga, Grabe, Tobias ORCID: 0000-0002-8287-1971, Mueller, Matthias P., Heuckmann, Johannes M., Klebl, Bert M., Nussbaumer, Peter, Sos, Martin L. and Rauh, Daniel (2022). Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors. J. Med. Chem., 65 (9). S. 6643 - 6656. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

Despite the clinical efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset of patients with non-small cell lung cancer displays insertion mutations in exon20 in EGFR and Her2 with limited treatment options. Here, we present the development and characterization of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1H-pyrrolo[2,3-b]pyridine scaffold. They exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion mutations as well as selectivity over wild type EGFR and within the kinome. Complex crystal structures with the inhibitors and biochemical and cellular on-target activity document their favorable binding characteristics. Ultimately, we observed tumor shrinkage in mice engrafted with patient-derived EGFR-H773_V774insNPH mutant cells during treatment with LDC8201. Together, these results highlight the potential of covalent pyrrolopyridines as inhibitors to target exon20 insertion mutations.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lategahn, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultz-Fademrecht, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimsoeth, AlenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Werr, LisaUNSPECIFIEDorcid.org/0000-0002-3697-4136UNSPECIFIED
Niggenaber, JaninaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parmaksiz, FatmaUNSPECIFIEDorcid.org/0009-0003-3771-7128UNSPECIFIED
Baumann, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menninger, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zent, EldarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landel, InaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisner, JoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jeyakumar, KirujanUNSPECIFIEDorcid.org/0000-0002-0184-6775UNSPECIFIED
Heyden, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russ, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, FabienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spille, IngaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grabe, TobiasUNSPECIFIEDorcid.org/0000-0002-8287-1971UNSPECIFIED
Mueller, Matthias P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klebl, Bert M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nussbaumer, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-683537
DOI: 10.1021/acs.jmedchem.1c02080
Journal or Publication Title: J. Med. Chem.
Volume: 65
Number: 9
Page Range: S. 6643 - 6656
Date: 2022
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LUNG; GEFITINIB; AZD9291; OSIMERTINIB; PREVALENCE; RESISTANCE; AFATINIB; NSCLCMultiple languages
Chemistry, MedicinalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68353

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