AMG 337

FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS.

Analysis of STMN1 serine (S)16, 25, 38, and 63 determined that total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1S16 alone can promote cell proliferation, and pSTMN1S16 shortens the cell cycle similar to HGF treatment, while STMN1S16 dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1S16 does not promote metastasis. Selectively inhibiting STMN1S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis.

Through rigorous molecular docking simulations utilizing Auto Dock Vina plugin integrated with Chimera software, Ketone (C29H56O) (IMPHY012701) emerged as a standout candidate, exhibiting a lower binding energy compared to the reference molecule, AMG 337 which was used as a control compound...Notably, Ketone (C29H56O) (IMPHY012701) demonstrated superior binding affinity relative to the control compound, underscoring its potential as a lead for further investigation. This study underscores the utility of computational approaches in drug discovery from natural sources and highlights Ketone (C29H56O) (IMPHY012701) as a promising candidate for the modulation of c-Met-mediated signalling pathways, warranting further experimental validation and exploration of its pharmacological properties.

P2, N=8, Terminated, NantPharma, LLC | Active, not recruiting --> Terminated; Prematurely terminated due to lack of therapeutic effect

P2, N=8, Active, not recruiting, NantPharma, LLC | Recruiting --> Active, not recruiting | N=37 --> 8 | Trial completion date: Jun 2021 --> Dec 2022 | Trial primary completion date: Mar 2021 --> Jun 2022

In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1...Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.