Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ATR Inhibitors as Potential Treatment for Cancers Ahmed F. Abdel-Magid* Therachem Research Medilab LLC, 100 Jade Park, Chelsea, Alabama 35043, United States Important Compound Classes:
>12 million new patients were diagnosed with cancer worldwide in 2008. The American Cancer Society data attribute >500,000 deaths to cancers in 2012 in the USA alone. There were also >1.6 million new diagnosed cancer cases in the same year with colon cancer, lung cancer, breast cancer, and prostate cancer being the most common. Currently, cancer is treated with chemotherapeutic agents and/or ionizing radiation. However, these treatments can induce DNA damage and may cause replication fork stalling, thereby activating cell cycle checkpoint pathways which lead to cell cycle arrest. Several studies have shown that this response is an important mechanism that helps cancer cells survive the treatments. These findings have prompted the development of alternative agents such as ATR inhibitors that can target the DNA damage response signaling pathways. Ataxia telangiectasia mutated and Rad3-related kinase (ATR) is a member of phosphatidylinositol kinase-related kinase (PIKK) protein family. It functions in conjunction with a regulatory partner protein named ATR-interacting protein (ATRIP). ATR is involved in detecting and repairing DNA damage and can be activated by a wide variety of DNA damage events. Particularly, it is activated to mediate DNA replicative stress (RS). RS occurs during DNA replication and can result in stalled replication forks and accumulation of single stranded DNA (ssDNA). The recombinogenic nature of ssDNA leads to chromosomal rearrangements that are a hallmark of cancer. ATR responds to RS by phosphorylation of checkpoint kinase 1 (CHK1) to trigger cell cycle arrest in the S, G2 and M stages. The ATR check-point response might help in limiting the expansion of precancerous cells undergoing RS as a result of oncogene activation. However, because the ATR-CHK1 checkpoint pathway serves to ensure cell survival after RS, a normal and robust ATR-CHK1 checkpoint may also be a mechanism of resistance to chemotherapy and that may allow cancer cells to survive with high endogenous levels of RS. Therefore, the inhibition of the ATR-CHK1 pathway may cause toxic effects on cells expressing oncogenes or lacking tumor suppressors through the generation of lethal amounts of RS that can lead to cancerous cell death. This sensitizing effect on the cancer cells may potentially assist the replication inhibitors acting as anticancer drugs by enhancing their effectiveness and lowering their doses. This would in turn, result in reduced toxicity to hematological and gastrointestinal organ systems among others. This treatment approach can only be useful if the normal cells are not sensitized to the same degree as cancer cells. Fortunately, the specificity of the replication inhibitor in causing cancer cell death may be assisted by the fact that normal cells have more robust S and G2 checkpoints than
Title. Tricyclic heterocylic derivatives Patent Application Number. WO 2017/202748 Al Publication Date. November 30th, 2017 Priority Application. EP 16171025.6 Priority Date. May 24th, 2016 Inventors. Burgdorf, L.; Dorsch, D.; Tsaklakidis, C. Assignee Company. Merck Patent GMBH; Frankfurter Strasse 250, 64293 Darmstadt (DE) Disease Area. Cancer Biological Target. Ataxia telangiectasia mutated and Rad3related kinase (ATR) Summary. The invention in this patent application relates to 8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene derivatives represented generally by formula I. These compounds are inhibitors of ATR and can potentially be useful for the treatment of different kinds of cancer. The cell-division cycle (including DNA replication) is a normal process that produces two identical daughter cells. The cell cycle contains four stages: the G1 phase, S phase, G2 phase and M phase. The overall process is controlled by three checkpoints that act as safeguards to ensure that the cells are ready to proceed to the next stage. Thus, unless the cells receive the proper signals to proceed to the next stage, they either wait for the necessary tasks to be completed or stop the cell cycle. These three checkpoints are • the G1 (cell restriction or start) checkpoint • the G2/M checkpoint • the metaphase checkpoint (a.k.a. the spindle checkpoint) During the DNA replication, the double helix unwinds and separates to allow the DNA polymerase enzymes to use each single strand as a template for the synthesis of a new double strand. Additionally, a number of helper proteins prevent the strands from coming back together during replication. The partial separation of the double helix forms what is known as a replication fork. Cancer is a generic term that describes a group of diseases resulting from uncontrolled cell division and growth in a wide variety of tissues. The cancerous cell growth may remain in the primary tissue and develop into a tumor, or it can also metastasize into remote organs. Cancer continues to be a very deadly disease. It is estimated that about 7.5 million people died from cancer while © XXXX American Chemical Society
Received: March 5, 2018
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DOI: 10.1021/acsmedchemlett.8b00107 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Data. The data obtained from testing the above represented examples are listed in the following table:
tumor cells. For example, many cancers have mutations in p53 or other components of the p53 pathway, leading to reliance on the S and G2 checkpoints to arrest the cell cycle and provide for repair and survival. Inhibition of the S and G2 checkpoints may then preferentially kill these p53 deficient tumor cells. Currently, there is a lack of potent inhibitors of ATR. Therefore, a need exists for new chemical entities that can selectively inhibit ATR for either clinical use or for further study of the ATR response. The compounds of formula I, described in this patent application, are inhibitors of ATR. These compounds were found to have very favorable pharmacological properties while being well tolerated. Therefore, they may potentially be used in the treatment of diseases in which the inhibition, regulation and/or modulation of ATR play a significant role such as cancer. Examples of cancers that can potentially be treated with ATR inhibitors include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors. and bloodborne tumors. Key Structures. The inventors described the structures and synthesis of 93 compounds of formula I, including the following representative examples:
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Recent Review Articles. 1) Sundar, R.; Brown, J.; Ingles, R. A.; Yap, T. A. Current Problems in Cancer 2017, 41 (4), 302−315. 2) Andrs, M.; Korabecny, J.; Nepovimova, E.; Jun, D.; Hodny, Z.; Kuca, K. Current Cancer Drug Targets 2016, 16 (3), 200−8. 3) Andrs, M.; Korabecny, J.; Nepovimova, E.; Jun, D.; Hodny, Z.; Moravcova, S.; Hanzlikova, H.; Kuca, K. Mini-Reviews in Medicinal Chemistry 2014, 14 (10), 805−811.
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The author declares no competing financial interest.
Biological Assays. • ATR/ATRIP Kinase Assay-Measurement of ATR/ ATRIP Inhibition • pCHK1 cellular assay • gH2AX-TopBP1ER cellular assay B
DOI: 10.1021/acsmedchemlett.8b00107 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
