Oncology
NXP900
SRC/YES1 Kinase Inhibitor
NXP900 is an oral small-molecule inhibitor targeting the SRC Family of Kinases (SFKs), with low nanomolar potency for SRC and YES1. It blocks both the catalytic activity and the scaffolding functions of the kinase.
- Oral small molecule
- Type 1.5 SRC/YES1 inhibitor
- Discovered at the University of Edinburgh
How it works
NXP900 locks the target kinase in its closed conformation, inhibiting both the catalytic and scaffolding functions of SRC and YES1. Approved and in-development multi-kinase inhibitors that target SRC inhibit only its catalytic function.
SRC/YES signaling is pro-oncogenic in solid tumors such as breast, colon, prostate, pancreatic and ovarian cancers. YES1 amplification is a mechanism of acquired resistance to targeted therapies, including TKIs and RAS inhibitors. NXP900 also inhibits YAP1 nuclear localization, which supports its use in cancers with Hippo pathway alterations such as FAT1 and NF2 mutations.
| Inhibitor | Inhibits kinase function | Inhibits scaffolding function | Inhibition of SRC/YES1 signaling |
|---|---|---|---|
| 1st Generation SRC/YES1 Inhibitors | Partial | ||
| NXP900 | Complete |
Clinical data
In a completed Phase 1a dose escalation in 33 patients with advanced solid tumors, given once daily at 20 to 300 mg, safety was acceptable and the dose-limiting toxicity level was not reached. About 90% inhibition of SRC phosphorylation was seen at 150 mg/day and higher. A separate drug-drug interaction study showed NXP900 is a weak CYP3A inhibitor, an important consideration for combination therapy.
Published preclinical research supports NXP900 in triple-negative breast cancer, in enzalutamide-resistant prostate cancer and, combined with osimertinib, in osimertinib-resistant lung cancer. NXP900 has also shown single-agent activity in ALK-resistant, YES1-amplified and FAT1-mutated models.