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Identification and validation of microtubule depolymerizing agent, CYT997, as a potential drug candidate for
Faiz Ahmad1, Li Ma1, Wei Wei1
1Asian Liver Center, Department of Surgery, School of Medicine, Stanford, California, USA.
Background And Aims:
Hepatocellular carcinoma (HCC) is a typically fatal malignancy with limited treatment options and poor survival rates, despite recent FDA approvals of newer treatment options. We aim to address this unmet need by using a proprietary computational drug discovery platform that identifies drug candidates with the potential to advance rapidly and successfully through preclinical studies.
Methods:
We generated an in silico model of HCC biology to identify the top 10 small molecules with predicted efficacy. The most promising candidate, CYT997, was tested for its in vitro effects on cell viability and cell death, colony formation, cell cycle changes, and cell migration/invasion in HCC cells. We used an HCC patient-derived xenograft (PDX) mouse model to assess its in vivo efficacy.
Results:
CYT997 was significantly more cytotoxic against HCC cells than against primary human hepatocytes, and sensitized HCC cells to sorafenib. It arrested cell cycle at the G2/M phase with associated up-regulations of p21, p-MEK1/2, p-ERK, and down-regulation of cyclin B1. Cell apoptosis and senescence-like morphology were also observed. CYT997 inhibited HCC cell migration and invasion, and down-regulated the expressions of acetylated tubulins, β-tubulin, glypican-3 (GPC3), β-catenin, and c-Myc. In vivo, CYT997 (20 mg/kg, three times weekly by oral gavage) significantly inhibited PDX growth, while being non-toxic to mice. Immunohistochemistry confirmed the down-regulation of GPC3, c-Myc, and Ki-67, supporting its anti-proliferative effect.
Conclusion:
CYT997 is a potentially efficacious and non-toxic drug candidate for HCC therapy. Its ability to down-regulate GPC3, β-catenin, and c-Myc highlights a novel mechanism of action.
Insights
Hepatocellular carcinoma (HCC) treatment shows promise with CYT997, a novel drug candidate demonstrating significant anti-cancer effects in preclinical studies. This compound effectively reduced tumor growth and exhibited a favorable safety profile in mouse models.
Area of Science:
- Oncology
- Drug Discovery
- Computational Biology
Background:
- Hepatocellular carcinoma (HCC) presents a significant unmet medical need due to limited treatment options and poor survival rates.
- Despite recent therapeutic advancements, effective treatments for HCC remain a challenge.
Purpose of the Study:
- To identify novel drug candidates for hepatocellular carcinoma (HCC) using a computational drug discovery platform.
- To evaluate the efficacy and mechanism of action of the lead compound, CYT997, in preclinical HCC models.
Main Methods:
- An in silico model of HCC biology was used to identify potential small molecule therapeutics.
- In vitro assays assessed CYT997's effects on HCC cell viability, apoptosis, cell cycle, and migration.
- In vivo efficacy was evaluated using a patient-derived xenograft (PDX) mouse model of HCC.
Main Results:
- CYT997 demonstrated significant cytotoxicity against HCC cells and sensitized them to sorafenib.
- The compound induced G2/M cell cycle arrest, apoptosis, and inhibited HCC cell migration and invasion.
- In vivo, CYT997 significantly inhibited PDX tumor growth without observable toxicity and downregulated key markers like GPC3, c-Myc, and Ki-67.
Conclusions:
- CYT997 is a promising, non-toxic drug candidate for HCC therapy.
- The drug's mechanism involves the downregulation of GPC3, β-catenin, and c-Myc, suggesting a novel therapeutic approach.
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