sovilnesib (AMG 650)

In line with this finding, both JAK1 knockout and kinase inhibition with abrocitinib prevented subsequent formation of radiation-induced micronuclei. Targeting the mitotic kinesin KIF18A with the small molecule sovilnesib exacerbated mitotic stress and enhanced the efficacy of radiation. These studies establish KIF18A inhibition as a strategy to counteract the protective G2/M cell cycle arrest induced by DNA damage and to thus enhance tumor cell sensitivity to radiation therapy.

We summarize the development of small-molecule inhibitors, from early compounds like BTB-1 to second-generation agents including Sovilnesib and VLS-1488, the latter currently in Phase I/II trials...New entrants like ATX-295 and GH2616 further expand the landscape...As clinical trials progress, optimizing patient stratification and exploring synergistic combinations will be crucial. Broadening the range of druggable sites on KIF18A, especially beyond the motor domain, could mitigate resistance and help expand therapeutic potential.

P1, N=120, Active, not recruiting, Volastra Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jul 2025 --> Apr 2026 | Trial primary completion date: Mar 2025 --> Mar 2026

A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650...Oral administration of 16 can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound 16 showed potential as a candidate for the clinical treatment of ovarian cancer.

P1, N=120, Recruiting, Volastra Therapeutics, Inc. | Not yet recruiting --> Recruiting | Phase classification: P1b --> P1

P1b, N=120, Not yet recruiting, Volastra Therapeutics, Inc.

In osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma models, antitumor activity of AMG 650 was variable, ranging from no objective responses to one model with a complete response. Identification of specific determinants of sensitivity and the evaluation of activity in combination will aid in potential use of AMG 650 in these pediatric tumor settings.

Lastly, the combination of AMG 650 with PARP inhibitor Olaparib enhances anti-cancer activity relative to single agent alone in BRCA1- and CCNE1-altered tumor models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via AMG 650, a first-in-class KIF18A inhibitor.

P1, N=66, Completed, Amgen | Active, not recruiting --> Completed | N=140 --> 66

P1, N=140, Active, not recruiting, Amgen | Trial completion date: Mar 2024 --> Feb 2023

P1, N=140, Active, not recruiting, Amgen | Trial completion date: Apr 2025 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Oct 2022

P1, N=140, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting