PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Inhibitors of the Antiapoptotic Myeloid Cell Leukemia‑1 (Mcl-1) May Provide Effective Treatment for Cancer Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Substituted Indole Mcl-1 Inhibitors
Patent Application Number: WO 2015/148854 Al Priority Application: US 61/971,023
Publication date: Priority date:
1 October 2015 27 March 2014
Inventors:
Lee, T.; Bian, Z.; Belmar, J.; Christov, P. P.; Pelz, N. F.; Shaw, S.; Kim, K.; Tarr, J. C.; Olejniczak, E. T.; Zhao, B.; Fesik, S. W.
Assignee Company:
Vanderbilt University, 305 Kirkland Hall, 2201 West End Avenue, Nashville, TN 37240, USA
Disease Area:
Cancer and disorders of the immune system
Summary:
The invention in this patent application relates to indole derivatives represented generally by formula (I) or formula (II). These
Biological Target:
Antiapoptotic myeloid cell leukemia-1 (Mcl-1) protein
compounds inhibit the activity of Mcl-1 antiapoptotic protein and may be useful for the treatment of diseases associated with overexpressed or dysregulated Mcl-1 protein such as cancer. The B-cell lymphoma 2 (Bcl-2) was the first discovered member of the Bcl-2 family of regulator proteins. Members of this family regulate apoptosis (programmed cell death) in two different mechanisms. Some family members (including Bax, Bak, Bad, Bid, Bim, Bmf, NOXA, and PUMA) function as pro-apoptotic by inducing apoptosis, while other members (including Bcl-2, Bcl-xL, Bcl-w, Bcl2-Al, and Mcl-1) function as antiapoptotic by inhibiting apoptosis. Under normal conditions, the pro-apoptotic and antiapoptotic members of the Bcl-2 family work together to tightly regulate the apoptosis process and maintain a balance between the two functions. The apoptosis regulation process is flexible and capable of altering this balance through increasing or decreasing the rate of apoptosis to respond effectively to stress, injuries, or other physiological demands. However, because of this ability to perform both tasks, a dysregulated process may contribute to the pathogenesis and progression of several disorders. For example, dysregulation may result in the survival of cells that would otherwise have undergone apoptosis such as cancer cells. Studies have shown that antiapoptotic Bcl-2 proteins are associated with a number of diseases, particularly cancer, immune, autoimmune diseases, and arthritis. Recent data implicates down-regulated apoptosis in the onset of cancer and show that antiapoptotic proteins are overexpressed in many cancer cell types. The overexpression of antiapoptotic Bcl-2 proteins in malignant cells enables these cells to resist apoptosis and survive under adverse conditions. It is also implicated in causing resistance to chemotherapy and disease progression in various cancers and disorders of the immune system. Thus, inhibition of the function of antiapoptotic Bcl-2 proteins may offer an effective strategy for the eradication of cancer cells. An emerging approach for cancer therapy is to activate the apoptotic pathway directly by either reducing the activity of antiapoptotic Bcl-2 proteins or enhancing the function of pro-apoptotic Bcl-2 proteins. It may therefore be advantageous to design small molecule inhibitors that can selectively target and preferably bind to one type or a subset of antiapoptotic Bcl-2 proteins. Selective inhibitors may also provide flexibility to select a dosing regimen to reduce on-target toxic effects in normal cells. Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic member of the Bcl-2 family. It is one of the most frequently overexpressed antiapoptotic genes in human cancers including prostate, lung, pancreatic, breast, ovarian, and cervical cancers, as well as melanoma, B-cell chronic lymphocytic leukemia (B-CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). The overexpression of Mcl-1 in cancer cells is implicated in resisting multiple cancer therapies including widely prescribed microtubule-targeted agents for breast cancers, such as paclitaxel and vincristine as well as gemcitabine, a first-line treatment option for pancreatic cancer. These data point out to the importance of Mcl-1 as a therapeutic target with a potential to treat a wide variety of cancers. There is a need for compounds that are capable of inhibiting the activity of Mcl-1 protein such as the compounds described in this patent application, which may be useful for the treatment of cancer and disorders of the immune system.
Received: November 14, 2015 Published: November 30, 2015 r 2015 American Chemical Society
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ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Important Compound Classes:
Key Structures:
The inventors listed the structures of 375 examples of formula (I) and formula (II) including the following representative compounds:
Biological Assays:
Assays for Bcl-2 Family Proteins Activity • Bak Peptide Binding Assay • Cellular Viability of Human Tumor Cell Lines • Apoptosis Assay Protocol (Caspase 3/7 Glo)
Biological Data:
The following tables contain some of the biological data obtained from testing the above representative examples
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ACS Medicinal Chemistry Letters Recent Review Articles:
PATENT HIGHLIGHT
1. Belmar, J.; Fesik, S. W. Pharmacol. Ther. 2015, 145, 76 84. 2. Gores, G. J.; Kaufmann, S. H. Genes Dev. 2012, 26 (4), 305 311. 3. Azmi, A. S.; Wang, Z.; Philip, P. A.; Mohammad, R. M.; Sarkar, F. H. Exp. Opin. Emerg. Drugs 2011, 16(1), 59 70. 4. Yip, K. W.; Reed, J. C. Oncogene 2008, 27, 6398 6406.
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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