Patent Highlight pubs.acs.org/acsmedchemlett
Modulation of the Inhibitors of Apoptosis Proteins (IAPs) Activities for Cancer Treatment Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
IAP Antagonists
Patent Application Number:
US 2016/0376307 A1
Publication date:
29 December 2016
Priority Application:
US 61/845,389
Priority date:
12 July 2013
Inventors:
Kim, K. S.; Zhang, L.; Stang, E. M.
Applicant:
Bristol-Myers Squibb Company, Princeton, NJ, USA
Disease Area:
Cancer
Summary:
The invention in this patent application relates to highly functionalized pyrrolidine-2-carboxamide derivatives represented generally by formula (I). These compounds modulate the activities of inhibitors of apoptosis proteins (IAPs) and may be beneficial in treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer.
Biological Target:
Inhibitors of apoptosis proteins (IAPs)
Apoptosis (programmed cell death) is a genetically controlled process designed to remove unwanted or damaged cells. The genes that coordinate apoptosis may suffer from disorders such as overexpression, mutation, or suppression and that links the apoptosis process to several diseases. There are two categories of diseases that may occur as a result of apoptosis disorders. The first category is associated with overactive apoptosis and that may lead to premature cell death, which is linked to a variety of developmental disorders. The second category is associated with deficiencies in apoptosis and the inhibition of cell death, which have been linked to cancer and chronic viral infections. Caspases (cysteine-aspartic proteases) constitute a family of proteases that play a key role in apoptosis. Caspases are strong proteases, and their activities need to be tightly controlled to prevent them from causing premature cell death. Therefore, they are highly regulated and their activities can be controlled by different mechanisms:
• Caspases remain in an inactive form called zymogen (proenzymes or inactive enzyme precursors) until they are activated by proteolytic processing at conserved aspartic acid residues.
• Caspases are regulated by a family of naturally occurring intracellular proteins known as Inhibitors of Apoptosis Proteins (IAPs). IAPs suppress the caspase-dependent apoptosis and can be found in different species such as virus, yeasts, flies, and mammals. A common structural feature in all IAPs is the presence of one to three copies of a zinc binding domain of about 70 amino acids known as Baculovirus IAP Repeat (BIR). Hence, IAPs are also called BIR-containing proteins (BIRCs). The BIR2 and 3 domains contain a conserved inhibitor of apoptosis binding motif (IBM) that can bind to and inhibit the proteolytic activity of caspases. There are eight known human IAP family members, namely: XIAP, cIAP1, cIAP2, ILP2, NAIP, BRUCE, Livin, and Survivin. Other IAP homologues were identified in numerous organisms. The baculovirus IAPs, including Cp-IAP and Op-IAP, were the first identified IAPs. The virus uses its IAPs to bind to and inhibit caspases in a mechanism that keeps the host cell alive long enough to complete its replication cycle. The most characterized human IAP is X-chromosome linked IAP (XIAP), which is expressed ubiquitously in most adult and fetal tissues. It inhibits the activities of caspases-3, -7, and -9 to prevent apoptosis. The BIR2 domain of XIAP inhibits caspases-3 and -7, while its BIR3 domain inhibits caspase-9 activation. IAPs are known to be overexpressed in many human cancers and may contribute directly to tumor progression and subsequent resistance to drug treatment. In addition, the levels of XIAP protein has been correlated to the rate of survival in patients with acute myelogenous leukemia. • In turn, the activities of IAPs are regulated by an intracellular protein known as pro-apoptotic protein Second Mitochondria-Derived Activator of Caspases (SMAC), also known as Direct IAP Binding Protein with low isoelectric point, pI (DIABLO). In normal healthy cells, SMAC and IAPs function together to maintain healthy cells. However, in certain disease states, e.g., cancers and other proliferative disorders, the activities of IAPs are not adequately modulated and therefore prevent apoptosis and cause or exacerbate abnormal proliferation and survival. SMAC is synthesized as a precursor protein molecule of 239 amino acids in the cytoplasm. Its N-terminal contains 55 amino acid residues that serve as a targeting sequence to the mitochondria. The 55 amino acid residues are removed upon import, and the mature SMAC, which resides in the intermembrane space of the mitochondria, will have a fresh N-terminus containing Ala1-Val2-Pro3-Ile4 (AVPI). The N-terminal AVPI residues are believed to play an important role in binding of SMAC to IAPs to stop their mediated inhibition of caspases. At the time of apoptosis, SMAC is released from mitochondria into the cytosol where, together with cytochrome c, it binds to XIAP to stop its inhibitory effect on caspases. In addition, SMAC binds the cellular IAP1 and 2 (cIAP1/2) to inhibit their ability to ubiquinate the receptor interacting protein kinases (RIPK). The ability of SMAC to interact with all examined IAPs showed its potential as a master regulator of apoptosis in mammals. Researchers have developed small molecule mimics of SMAC that function as IAP antagonists. These molecules mimic the structure and IAP modulating activity of the four N-terminal amino acids of SMAC (AVPI). When these compounds were administered to patients suffering from proliferative disorders, they cause an increase in apoptosis in abnormally proliferating cells.
Received: March 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00148 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters Summary (continued):
Patent Highlight
In vitro and in vivo studies have shown that down-regulation of XIAP expression by antisense oligonucleotides induces sensitization of tumor cell death by a wide range of pro-apoptotic agents. Additionally, SMAC/DIABLO-derived peptides show that they can sensitize a number of different tumor induced select cell lines to undergo apoptosis either as single agents or with the help of additional stimuli such as death receptor (DR) agonists or cotreatment with proapoptotic drugs. Therefore, the inhibition of IAPs appears to be a viable mechanism for promoting apoptosis and treating diseases and conditions that are sensitive to apoptosis. Consequently, there exists a continuing need to develop compounds such as the ones described in this patent application that can inhibit IAP and may provide effective treatments of diseases resulting from apoptosis disorders, such as cancer.
Important Compound Classes:
Key Structures:
The inventors described the structures and synthesis procedures of eight examples of formula (I) including the following examples:
B
DOI: 10.1021/acsmedchemlett.7b00148 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters Biological Assay:
Patent Highlight
1. XIAP-BIR3/SMAC Homogeneous Time Resolved Fluorescence (HTRF) Assay 2. XIAP-BIR2−3 dimeric SMAC Peptide Homogeneous Time Resolved Fluorescence (HTRF) Assay
Biological Data:
The data obtained from testing the above examples using the biochemical binding assays are listed in the following table:
Recent Review Articles:
Oberoi-Khanuja, T. K.; Murali, A.; Rajalingam, K. Cell Death Dis. 2013, 4 (Sept.), e784. Tewari, K. M.; Dhaneshwar, S. S. J. Can. Res. Updates 2012, 1 (2), 212−22. Smolewski, P.; Robak, T. Curr. Mol. Med. 2011, 11 (8), 633−649.
■
Lladser, A.; Sanhueza, C.; Kiessling, R.; Quest, A. F. G. Adv. Cancer Res. 2011, 111, 1−37.
AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00148 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
