Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
2,7-Diazaspiro[4,4]nonanes for the Treatment or Prevention of Cancers and Diabetes Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States Important Compound Classes.
partner genes, such as AF4, ENL and AF9, led to complexes that bind to promoters that stimulate aberrant gene expression. Growing clinical evidence suggests that the fusion partner of MLL-1 is a major determinant of the ultimate leukemia phenotype. For example, MLL-AF9 more often results in myeloid malignancies, whereas MLL-AF4 is associated with lymphoid malignancies. The functional stimulation of MLLfused proteins is highly dependent on the interaction with an essential oncogenic cofactor, namely, menin protein, which takes place at the conserved N-terminal region. For instance, menin protein interaction is essential for MLL fusion protein leukemogenesis. In downstream expression, the menin-binding motifs (MBM1 and MBM2) bind via the MLL N-terminal region and interact with a large cavity within the menin protein. Menin proteins are ubiquitously expressed in various levels within a number of tissues in varying proportions. They are primarily a nuclear protein and also detectable in the cytoplasm and cell membrane. Furthermore, menin-interacting proteins can be classified into four main categories based on their cellular functions: transcription activators and repressors, cell signaling, regulation of DNA repair, and structural integrity of the cells. In addition, about 10% of all leukemias harbor the MLL-1 translocations. There are loosely three patient populations in this category; patients younger than 1 year of age, young-tomiddle-aged adults, and patients with MLL-1 rearrangements, which are associated with chemotherapeutic agents. Menin proteins are implicated in a number of disease processes. Prostate cancer is commonly diagnosed and is a leading cause of cancer-related deaths. Association of menin and prostate cancer implies the direct interaction with the androgen receptor (AR) in the N-terminal domain. In vivo and in vitro models have shown that disruption of the menin-MLL interaction inhibits the AR pathway and reduces the proliferation of prostate cancer. Menin is also implicated in breast cancer, which is one of the leading causes of cancer-related deaths in women worldwide. Menin directly binds to the estrogen receptor (ER) to promote MLL recruitment, which stimulates H3K4 methylation and regulates the expression of estrogen target genes. Consequently, menin inhibitors may reduce the proliferation of breast cancer. There are a number of other disease processes that menin proteins are implicated, including but not limited to multiple endocrine neoplasia type 1, hyperglycemia, and hepatocellular carcinoma. The present data point to a very strong evidence that menin is a coactivator for a number of enzymes and transcription enzymes involved in regulation of cellular
Title. 2,7-Diazaspiro[4,4]nonanes Patent Application Number. WO 2018/024602 A1 Publication Date. February 08, 2018 Priority Application. EP 16182691.2 Priority Date. August 04, 2016 Inventors. Siegel, S.; Haendler, B.; Stresemann, C.; Fernandez-Montalvan, A. E.; Ter Laak, A.; Stöckigt, D.; Harb, H. Y.; Kosemund, D.; Eheim, A.; Mönning, U. Assignee Company. Bayer Company and Bayer Pharma Company. Disease Area. Cancer and diabetes Biological Target. Menin and mixed lineage leukemia (MLL) proteins. Summary. Protein−protein interactions (PPIs) play a critical role in many biological processes, and existing proofof principles that small molecule inhibitors of PPIs may serve as therapeutic target have necessitated increasing efforts in developing a viable drug-like molecule that inhibits PPIs. However, identifying small molecule inhibitors of PPIs has been challenging due to the lack of well-defined binding pockets, the flexibility of residues within the protein interfaces, the vast interacting areas, and the large molecular weight of PPI inhibitors that may be required to achieve high levels of potency, and so forth. In spite of these formidable challenges, there are a number of successful examples of small molecule inhibitors of PPI that have advanced to clinical evaluations. The PPI between mixed lineage leukemia (MLL) and menin plays an essential role in acute leukemias with translocations of the MLL gene, and inhibition of this interaction represents novel potential therapeutic strategy for MLLs. MLLs represent a large class of proteins that lack a well-defined threedimensional structure in isolation. However, when they bind to their physiological ligands, they undergo orderly transition. The MLL gene encodes a histone methyltransferase, which is responsible for methylation of histone 3 at lysine 4 on chromatin. The rearrangement of the MLL gene has been implicated in many cancers. A subgroup of MLL protein, namely, MLL-1, is characterized by fusion to different partners at their N- or C-terminal end. In addition, the fusion at the Nterminal of MLL proteins with one of more than 80 different © XXXX American Chemical Society
Received: April 5, 2018
A
DOI: 10.1021/acsmedchemlett.8b00159 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Assay. The biological activity of compounds in this invention were tested in multiple biological assays. The in vitro activities (TR-FRET) were demonstrated by the ability of the compounds to disrupt the interaction of Menin and MLL-1, which gives a measure of their menin-binding affinities. For leukemia models, MV4-11 and MOLM-13 cell proliferation assays were used, which determine the ability of the compounds to inhibit cell proliferation. Cell viability was determined by alamarBlue reagent. For prostate cancer models, LAPC-4 and LNCaP cell proliferation assays were used. Cell viability were determined by CellTiter-Glo and the measurement of luminescence. For breast cancer models, MCF7 and MDA-MB-468 cell proliferation assays were used. Cell viability were determined by CellTiter-Glo and the measurement of luminescence. Biological Data. The table below shows result of the inhibition in the menin/MLL-1 assay (IC50 is the concentration of test compound needed for 50% inhibition of cell proliferation).
activities. Consequently, its function is deregulated in tumors and other diseases where menin interacts with transcription factors. It should be noted that the therapeutic outcomes for menin-MLL fusion in patients remain poor when compared to patients with non-MLL-1 rearranged leukemias. However, small molecule inhibitors have been described including thienopyrimidines, hydroxy- and aminomethylpiperidine, and so forth. Compounds of this invention are found to be an effective inhibitor of the interaction between menin and MLL-1, and could be used for the treatment of menin related disorders such as hepatocellular carcinoma, diabetes, and breast and prostate cancers. Definitions. X represents some selections from
R1 = H or Me; R2 = H, F, Cl, OH, or OMe; R3 = H, F, Cl, OH, Me, CN, and so forth. R4 = H, OH, halogen, CN, C1−C3-alkyl, C1−C3-haloalkyl, C1−C3-alkoxy, and so forth. R5 = H, Me, or Cl; R7, R8 = H, C1−C3-alkyl, C2−C3-hydroxyalkyl, −(SO2)phenyl, and so forth; R9 = CN, −CO2H, −(CO)−O−C1−C3-alkyl, etc. R10 = C1−C4-alkyl, C1−C4-haloalkyl, methoxy-C1−C4-alkyl, etc. R11 = C1−C4-alkyl; R12, R13 = H, C1−C4-alkyl, C3−C6-cycloalkyl, C1−C4haloalkyl, and so forth. R14 = H or Me. Key Structures.
■
Recent Review Articles. 1. Wang, Z.-H.; Li, D.-D.; Chen, W.-L.; You, Q.-D.; Guo, X.-K. Bioorg. Med. Chem. 2018, 26, 356−365. 2. Winter, A. C.; Bernt, K. M. Front. Pediatr. 2017, 5, 1−21. 3. Zhu, H.; Sun, A. J. Mol. Cell. Cardiol. 2018, 116, 125− 134. 4. Seifert, L.; Miller, G. Clin. Cancer Res. 2017, 23, 1132− 1136.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
B
DOI: 10.1021/acsmedchemlett.8b00159 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
