Vrn10, Discovery Of Potent Irreversible Her2 Kinase Inhibitors With Intracranial Activity.

Abstract Human epidermal growth factor receptor 2 (HER2) amplification is one of oncogenic drivers most found in breast cancer but also occurs in multiple other tumor types. Approximately 10-30% of patients with breast cancer develop brain metastases (BCBM), a devastating cause of morbidity and mortality. To address this unmet medical need, VRN10s, brain penetrant, orally bioavailable, and irreversible small molecule inhibitors were designed to target HER2 while sparing EGFR wild type. In biochemical assays VRN10s had low nanomolar potency to inhibit catalytic activity of HER2. In cell viability assays using HER2+ breast and gastric cancer cell lines, VRN10s inhibited proliferation with single-digit nanomolar potency and exhibited an exceptional selectivity for HER2 over EGFR, with an enhancement of > 30-fold. Neuregulin-1 (NRG-1) has been suggested to decrease the anti-tumor activity of HER2 kinase inhibitors by induction of HER3 in brain microenvironment. Two FDA-approved HER2 kinase inhibitors tucatinib and lapatinib are not only less brain permeable, but they also show significantly decreased activity in the presence of NRG-1. However, the addition of NRG-1 did not rescue the proliferation of HER2+ breast cancer cell lines treated with VRN10s. Western blot confirmed that VRN10s inhibit signal transduction downstream of HER2 and HER3 through the AKT and ERK pathways. Inhibition of HER2 is reported to cause cytotoxicity on cardiomyocytes. In spite of potent inhibition of HER2 catalytic inhibition, VRN10s did not show cardiomyocyte cytotoxicity more than other HER2 kinase inhibitors, including tucatinib and neratinib. We confirm VRN10s to have high brain exposure in several preclinical models. Consistent with our in vitro results, potent activity was observed in the xenograft and intracranial models using once daily oral administration with strong tumor growth inhibition. Based on in vitro assay, brain permeability and in vivo efficacy, VRN10s may be promising therapeutic candidates for patients with HER2+ tumors including BCBM. Citation Format: Hwan Kim, Younho Lee, Jinhee Park, Youngyi Lee, Jieun Choi, Jihye Yoo, Chanmi Park, Somi Lee, Eunhwa Ko, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB139.