Imidazo[4,5-c]quinoline Compounds and their use for the Treatment of ATM Mediated Diseases, Especially Cancer
Molecules for extremely efficient inhibition of ATM with good aqueous solubility, metabolic stability and a favorable selectivity profile
ATM kinase, a serine threonine kinase involved in a plurality of key cellular functions, plays a major role in the DNA damage response (DDR) pathways. This kinase responds directly to double-strand breaks (DSBs) caused by common anti-cancer treatments such as ionizing radiation, topoisomerase-II inhibitors but also topoisomerase-I inhibitors. ATM kinase inhibitors can potentiate the activity of these agents and are therefore expected to be a useful combination partner in the treatment of cancer.
The underlying invention provides compounds that are effective in inhibiting, regulating and/or modulating ATM kinase, in particular compounds that have an increased inhibitory effect against ATM kinase. Furthermore, the compounds are effective in treatment of cancer, in particular colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphatic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.
ATM kinase is a serine threonine kinase which was originally identified as the product of the gene mutated in ataxia telangiectasia. ATM kinase belongs to the PIKK family of kinases having domains with homology to phosphoinositide kinases. These kinases are involved in a plurality of key cellular functions, such as cell growth, cell proliferation, migration, differentiation, survival and cell adhesion. ATM kinase responds to direct double-strand breaks caused by common anti-cancer treatments such as ionizing radiation, topoisomerase-II inhibitors but also topoisomerase-I inhibitors. ATM kinase inhibitors can potentiate the activity of these agents and are therefore expected to be useful in the treatment of cancer.
The compounds are based on a tricyclic imidazo[4,5-c]quinolone scaffold, which has already been applied earlier in the development of ATM kinase inhibitors. Along with a extremely efficient inhibition of the target kinase, these newly developed compounds also display additional drug-like properties e.g. good aqueous solubility, metabolic stability and a favorable selectivity profile.
Stage of Development
Biological evaluation of the compounds:
- Calculation of the IC50 value with an enzymatic ATM assay
- Calculation of the IC50 value in two different cancer cell lines
Teodor Dimitrov, Cetin Anli, Athina Anastasia Moschopoulou, Thales Kronenberger, Mark Kudolo, Christian Geibel, Martin Peter Schwalm, Stefan Knapp, Lars Zender, Michael Forster, Stefan Laufer: Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity. European Journal of Medicinal Chemistry, Volume 114234, 23 May, 2022. https://doi.org/10.1016/j.ejmech.2022.114234
- Compounds for effective inhibition, regulation and/or modulation of ATM kinase
- Compounds are effective in treatment of cancer as confirmed in two pancreatic cancer cell lines
- Compounds have better efficacy based on in vitro data compared to already available ATM kinase inhibitors. Biochemical IC50 in single digit nanomolar range and cellular IC50 in nanomolar to micromolar range
- Targeted therapy of ATM mediated diseases, especially cancer.
- Adjuvant therapy to all radiation treated cancers
- Adjuvant therapy to treatments, which intentionally induce double-strand breaks
- Priority patent application “Imidazo[4,5-c]quinoline Compounds and their use as ATM Kinase Inhibitors” EP20205316.1 filed. Applicant: DKFZ, Uni Tübingen, Uniklinik Tübingen
- Patent application WO 2022/096361 “Imidazo[4,5-c]quinoline Compounds and their use as ATM Kinase Inhibitors” filed.
- Patent application submitted
- Development partner