Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Wilding, Birgit; Scharn, Dirk; Böse, Dietrich; Baum, Anke; Santoro, Valeria; Chetta, Paolo; Schnitzer, Renate; Botesteanu, Dana A; Kornigg, Stefan; Knesl, Petr; Hörmann, Alexandra; Köferle, Anna; Corcokovic, Maja; Lieb, Simone; Scholz, Guido; Bruchhaus, Jens; Spina, Markus; Balla, Josef; Peric-Simov, Biljana; Zimmer, Jasmin; Mitzner, Sophie; Fett, Thomas N; Beran, Alexandra; Lamarre, Lyne; Gerstberger, Thomas; Gerlach, Daniel; Bauer, Markus; Bergner, Andreas; Schlattl, Andreas; Bader, Gerd; Treu, Matthias; Engelhardt, Harald; Zahn, Stephan K.; Fuchs, Julian E.; Zuber, Johannes; Ettmayer, Peter; Pearson, Mark; Petronczki, Mark; Kraut, Norbert; McConnell, Darryl B.; Solca, Flavio; Neumüller, Ralph A.

doi:10.1038/s43018-022-00412-y

Cited by 13 publications

(17 citation statements)

References 57 publications

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“…The estimated distance of 25 nm between the coil on the N‐terminus and the DNA strand on the nanobody bound to the C‐terminus of the Her2 receptor, was determined by adding up distances measured from crystal structures of Her2. In fact, we measured 8 nm for the ECD (PDB IN8Z), [ 28 ] 6 nm for the transmembrane domain (PDB 2N2A), [ 29 ] estimated 5 nm for the ICD (PDB 7PCD), [ 30 ] 3 nm for the CFP (PDB 2HQK), [ 31 ] and 3 nm for the anti‐GFP nanobody (PDB 3K1K). [ 32 ]…”

Section: Resultsmentioning

confidence: 99%

Optimized Coiled‐Coil Interactions for Multiplexed Peptide‐PAINT

Eklund

Jungmann

2023

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Super‐resolution microscopy has revolutionized how researchers characterize samples in the life sciences in the last decades. Amongst methods employing single‐molecule localization microscopy, DNA points accumulation for imaging in nanoscale topography (DNA‐PAINT) is a relatively easy‐to‐implement method that uses the programmable and repetitive binding of dye‐labeled DNA imager strands to their respective docking strands. Recently developed Peptide‐PAINT replaces the interaction of oligonucleotides by short coiled‐coil peptide sequences leading to an improved labeling scheme by reducing linkage errors to target proteins. However, only one coiled‐coil pair is currently available for Peptide‐PAINT, preventing multiplexed imaging. In this study, the initial Peptide‐PAINT E/K coil is improved by modifying its length for optimized binding kinetics leading to improved localization precisions. Additionally, an orthogonal P3/P4 coil pair is introduced, enabling 2‐plex Peptide‐PAINT imaging and benchmarking its performance and orthogonality using single‐molecule and DNA origami assays. Finally, the P3/P4 peptide pair is used to image the human epidermal growth factor receptors 2 (ErbB2/Her2) in 2D and 3D at the single receptor level using genetically encoded peptide tags.

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Section: Resultsmentioning

confidence: 99%

Optimized Coiled‐Coil Interactions for Multiplexed Peptide‐PAINT

Eklund

Jungmann

2023

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“…Notably, EGFR T854A has previously been associated with resistance to EGFR inhibitors [48][49][50] . HER2 T862A is also resistant to BI-1622, a novel HER2 inhibitor shown to directly interact with S783 51 . Based on computational structural studies for HER2 mutations, we have shown that neratinib directly interacts with T862 and S783 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Marín

Mamun

Akamatsu

et al. 2022

Preprint

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HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.

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“…Column chromatography separations were performed with silica gel (200−300 mesh). Target compounds were identified by 1 H NMR and 13 C NMR spectra and high-resolution mass spectra (HRMS) with purity >95% (see details in the Supporting Information).…”

Section: ■ Conclusionmentioning

confidence: 99%

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases

Yang,

Li,

et al. 2024

J. Med. Chem.

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HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

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Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Cited by 13 publications

References 57 publications

Optimized Coiled‐Coil Interactions for Multiplexed Peptide‐PAINT

Optimized Coiled‐Coil Interactions for Multiplexed Peptide‐PAINT

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases

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