BI 853520: Targeted PTK2 Inhibition and Its Anticancer Efficacy in Xenograft Models

The PTK2/FAK enzyme, a non-receptor tyrosine kinase, is crucial in cell processes such as survival, proliferation, and movement due to its role in focal adhesions and its response to signals from growth factor receptors and integrins. It is often overexpressed in various cancers, and its abnormal regulation can lead to the uncontrolled growth of cancerous cells. Targeting PTK2 could therefore be a potential strategy to combat tumor growth and metastasis.

BI 853520 is a compound that has been shown to inhibit PTK2's enzymatic activity at very low concentrations. It has been tested for selectivity and found to be highly specific, inhibiting only a few enzymes significantly among a panel of over 260 kinases. This high selectivity distinguishes it from other PTK2 inhibitors and suggests a lower likelihood of off-target effects.

In vitro studies using human PC-3 prostate cancer cells, which naturally have high levels of PTK2, demonstrated that BI 853520 effectively inhibits the enzyme's autophosphorylation at extremely low concentrations and reduces colony formation in soft agar, indicative of a reduced ability to grow independently of anchorage—a characteristic of malignant cells. However, the compound required much higher concentrations to inhibit growth in a conventional monolayer culture, a finding that was consistent across other carcinoma cell lines.

In vivo studies in immunodeficient mice showed that BI 853520 has excellent oral bioavailability and a relatively long half-life. It was well tolerated even at high doses and effectively suppressed PTK2 autophosphorylation in both human tumor xenografts and mouse skin. When tested across a range of human tumor xenograft models, BI 853520 exhibited significant anti-tumor activity at doses as low as 6 mg/kg, indicating a broad therapeutic window. Notably, it was highly effective in certain models, such as the PC-3 prostate carcinoma, leading to substantial suppression or even regression of tumor growth.

The compound's efficacy was variable across different tumor types, with some showing strong responses and others being resistant. Ongoing research is aimed at identifying biomarkers that could predict sensitivity to BI 853520, focusing on genetic mutations, gene expression patterns, and phosphoproteome profiles of the tumors.

In summary, BI 853520 is a novel and highly selective PTK2 kinase inhibitor that has demonstrated both in vitro and in vivo anti-tumor activity. Clinical trials for this compound have recently begun, offering a promising new approach for cancer treatment.