Mutant Her2 (Neu/ErbB2) is a driver of non-small cell lung cancer (NSCLC) in 4% of the patients 132 or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. Afatinib is also under investigation as a monotherapy in patients with HER2-positive breast cancer who had progressed despite trastuzumab treatment. 134 Neratinib (Puma) potently inhibits HER2 by covalently binding Cys805 (a cysteine residue homologous to Cys797 in EGFR) and was approved by the FDA for treatment of HER2 + breast cancer in 2017. Dacomitinib (Vizimpro ® ) is an orally administered, small-molecule irreversible inhibitor of HER1 (EGFR), HER2 and HER4 that was developed by Pfizer Inc. In September 2018, dacomitinib received its first global approval by US FDA, for use in the first-line treatment of patients with EGFR-mutated metastatic NSCLC. Data from Phase II clinical trials indicate that poziotinib, a covalent HER2 inhibitor developed by Spectrum Pharmaceuticals, may be a useful treatment for metastatic lung cancers harboring HER2 exon 20 insertion mutations. 138 138 However, in November 2022 the US FDA denied approval for the use of poziotinib based on the current clinical trial data and asked for data from additional trials. The most recently reported covalent HER2 inhibitors were pyrrolopyrimidines discovered by focused compound screening and structure-based drug design (SBDD). One of the identified compounds inhibited H1781 cancer cells with an IC50 value of 161 nM. The compound showed favorable physicochemical and pharmacokinetic profiles comparable to that of neratinib and established the pyrrolopyrimidine core as a suitable scaffold for covalent inhibition of Her2. 140