Quercetin-3-rhamnoside, quercetin-3-glucoside, quercetin-3-O-galactoside, and quercetin-3-rutinoside demonstrated superior binding affinities (-9.5 to -11.089 kcal/mol) compared to control drug Luvixasertib (-8.869 kcal/mol), with enhanced electronic properties (electrophilicity index: 3.53-4.67 compared to control 2.70)...Additionally, toxicity profiling revealed favorable safety profiles with no hepatotoxic, carcinogenic, or mutagenic potential for most derivatives. Therefore, Quercetin derivatives from A. indica leaf represent promising lead compounds for targeted TTK inhibitors in lung and pancreatic adenocarcinomas, highlighting their potential for further experimental validation against TTK.

Loss of PRR14L prolongs SAC-dependent mitotic arrest in response to microtubule depolymerization but, paradoxically, leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors. A model derived from our findings provides a rationale for exploiting MPS1 inhibition as a potential vulnerability in cancers containing either PRR14L loss of function mutations or FGFR-TACC3 fusions.

P1/2, N=90, Completed, Nerviano Medical Sciences S.r.l. | Active, not recruiting --> Completed

However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics.

P1/2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2025 --> Dec 2026

P1, N=260, Recruiting, SillaJen, Inc. | Trial completion date: Mar 2026 --> Dec 2026 | Trial primary completion date: Jul 2025 --> Dec 2026

Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.

P1/2, N=44, Active, not recruiting, Treadwell Therapeutics, Inc | Recruiting --> Active, not recruiting | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2025 --> Aug 2026

P1/2, N=31, Terminated, Nerviano Medical Sciences | Completed --> Terminated; In the Phase II part of the study, among the participants evaluable for efficacy, no objective (partial response or clinical response) was observed at the first futility analysis.

P1/2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2024 --> Dec 2025

CFI-402257, a specific inhibitor of TTK, is found to exhibit anti-tumor effects and exerted synergistic efficacy with PI3K inhibitor, Duvelisib, in TCL. The study shows that TTK contributes to the development of TCL by regulating p38α-mediated AMPK/mTOR pathway. CFI-402257 is expected to be a promising strategy for TCL treatment.

The TP53MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance. Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in gastric cancer cells and investigates its mechanism of action.