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

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.

Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis.

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.

Plasma concentrations and analgesic effects of ropivacaine 3.75 mg/ml during long-term extrapleural analgesia after thoracotomy.

BACKGROUND AND OBJECTIVES: Fourteen patients received long-term extrapleural analgesia with ropivacaine for postoperative pain relief after posterolateral thoracotomy. We determined plasma concentrations of ropivacaine as well as pain scores and opioid consumption to assess the analgesic effect. METHODS: In this prospective study, an extrapleural catheter was placed with its tip near the third rib before chest closure. The extrapleural block started with 10 mL of 7.5 mg/mL of ropivacaine followed 30 minutes later by an infusion of 3.75 mg/mL of ropivacaine at a fixed rate of 0.1 mL/kg/h for 71.5 hours. RESULTS: Mean total and free ropivacaine concentrations increased until day 1, reached similar values on day 2, and subsequently decreased. In 13 patients, free drug levels did not exceed 0.14 mg/L. Coincidence of above-average total ropivacaine concentrations up to 4.8 mg/L and low plasma binding resulted in free drug concentrations up to 0.31 mg/L in 1 patient. An impaired ropivacaine plasma binding was observed in 2 patients after major surgical blood loss, in 3 patients in a state of a moderate postoperative acidosis, and in 1 patient after intravenous administration of clindamycin. All free ropivacaine concentrations measured were below the toxic threshold, and we observed no clinical signs of ropivacaine-related toxicity. The magnitude of pain scores and the opioid consumption pointed out a sufficient postoperative analgesia. CONCLUSIONS: A dose of 0.375 mg/kg/h of ropivacaine can safely be administered for long-term extrapleural analgesia after thoracotomy.