By a News Reporter-Staff News Editor at Biotech Week According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Ebeling, Martin (Grenzach-Wyhlen, DE); Metzger, Friedrich (Freiburg, DE); Sivaramakrishnan, Manaswini (Basel, CH), filed on February 19, 2016, was made available online on August 31, 2017 (see also Pharmaceutical Companies).
The assignee for this patent application is Hoffmann-La Roche Inc.
Reporters obtained the following quote from the background information supplied by the inventors: "FoxM1 is a transcription factor of the Forkhead family. It is also known in the literature as Trident (in mouse), HFH-11 (in human), WIN or INS-1 (in rat), MPP-2 (partial human cDNA) or FKHL-16. The Forkhead family comprises a large number of transcription factors defined by a conserved DNA binding domain called Forkhead or winged-helix domain. The FoxM1 gene was cloned by screening cDNA libraries with degenerate primers for homologues with a conserved Forkhead DNAbinding domain (W. Korver, J. Roose, H. Clevers, Nucleic Acids Res. 25 (1997) 1715-1719). The FoxM1 gene was revealed to encode a Forkhead transcription factor family member that exhibits 45% identity in the DNA-binding domain with five of its closest related Forkhead members, namely FoxA3 (HNF-3.gamma., FoxC1 (fkh-1), FoxF2 (FREAC-2), FoxK1 (ILF) and FoxN2 (HTLF). The FoxM1 C-terminal region was found to have homology (76% identity) with a human partial cDNA encoding an open reading-frame of 221 amino acids, termed MPP-2. MPP-2 stands for MPM-2-reactive phosphoprotein-2 and was identified after screening a lymphoblast-derived cDNA library with the MPM-2 monoclonal antibody, which binds specifically to epitopes on mitotic proteins that are phosphorylated in a phosphoserine-proline dependent manner. FoxM1 binds DNA in vitro through the consensus site TAAACA. This motif shares the core sequence recognized by other members of the forkhead family. In particular, repeats of these motifs, in alternating orientation, were often characterized within the selected binding sequences for FoxM1.
"The human FoxM1 gene is a 10-exon structure spanning approximately 25 kb on the 12p13-3 chromosomal band (telomeric position) (W. Korver, J. Roose, H. Clevers, Nucleic Acids Res. 25 (1997) 1715-1719). Two exons, named exons Va and VIIa, also referred to as exon A1 (or rat exon 6) and A2 respectively, are alternatively spliced (H. Ye, T. F. Kelly, U. Samadani, L. Lim, S. Rubio, D. G. Overdier, K. A. Roebuck, R. H. Costa, Mol. Cell Biol. 17 (1997) 1626-1641). Exon Va encodes a 15 amino-acid insertion within the C-terminal part of the DNA binding-domain, and is not seen in any of the other Forkhead transcription factor family members. Exon VIIa represents a 38 amino-acid insertion within the C-terminus of the protein. Differential splicing of exons Va and VIIa in human FoxM1, gives rise to three classes of transcripts, class A containing both alternative exons, class B containing none of the alternative exons, and class C in which exon Va only is retained (H. Ye, T. F. Kelly, U. Samadani, L. Lim, S. Rubio, D. G. Overdier, K. A. Roebuck, R. H. Costa, Mol. Cell Biol. 17 (1997) 1626-1641). Both FoxM1B and FoxM1C are transcriptionally active, whereas FoxM1A is transcriptionally inactive, due to the insertion of exon VIIa in the C-terminal transactivation domain. This disruption of the transactivation domain in FoxM1A not only leads to transcriptional inactivation, it might also cause this variant to act as a dominant-negative variant as it has retained normal DNA binding activity in the absence of a functional transactivation domain (H. Ye, T. F. Kelly, U. Samadani, L. Lim, S. Rubio, D. G. Overdier, K. A. Roebuck, R. H. Costa, Mol. Cell Biol. 17 (1997) 1626-1641).
"FoxM1 is overexpressed in a broad range of tumor types, including those of neural, gastrointestinal, and reproductive origin (see Bektas et al., supra; Nakamura et al., 2004, Oncogene 23: 2385-400; Pilarsky et al., 2004, Neoplasia. Q: 744-50; Liu et al., 2006, Cancer Res 66: 3593-602). This expression pattern of FoxM1 is attributed to the ability of FoxM1 to transactivate genes required for cell cycle progression (Wang et al., 2002, Proc Nat. Acad Sci USA 99:16881-6). Increased nuclear staining of FoxM1B found in human basal cell carcinomas suggests that FoxM1 is required for cellular proliferation in human cancers (Teh et al., 2002, Cancer Res. 62: 4773-80). The detailed role of FoxM1 in establishing or facilitating tumor progression and disease management has not been fully elucidated, however.
"EP 2 298 896 discloses siRNA molecules inhibiting expression of FoxM1B protein and the use of the siRNA molecules for inhibiting tumor growth.
"WO 2011/127297 discloses a composition comprising a FoxM1 inhibitor and Herceptin for the treatment of breast cancer. The inhibitor is for example a FoxM1 specific siRNA or a thiazole antibiotic such as thiostrepton.
"The problem to be solved by the present invention was to provide new compounds for the treatment of cancer."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "In a first aspect the present invention provides compounds inducing alternative splicing of the FoxM1 gene (splicing modifiers) for use in the prophylaxis or treatment of cancer, wherein the compound induces a transcriptionally inactive FoxM1 variant.
"In a particular embodiment, the transcriptionally inactive FoxM1 variant is FoxM1A.
"In a particular embodiment, the FoxM1 gene is the human FoxM1 gene.
"In a particular embodiment, the cancer is selected from the group consisting of cancer of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system.
"In a particular embodiment, the FoxM1 splicing modifier for use in the prophylaxis or treatment of cancer is a compound of formula I:
"wherein R.sup.1 is selected from aryl, heteroaryl, heterocycloalkyl, which all three substituents are optionally substituted by C.sub.1-7 alkyl, C.sub.1-7 alkoxy, C.sub.1-7 haloalkoxy, C.sub.1-7haloalkyl, halogen, hydroxyl, cyano, NO.sub.2;
"R.sup.2 is C.sub.1-7 alkoxy optionally substituted by heterocycloalkyl, NR'R'', or heterocycloalkyl optionally substituted by hydroxy, NR'R''C.sub.1-7 alkyl, hydroxy-C.sub.1-7 alkyl, C.sub.3-8 cyclopropyl, heterocycloalkyl, C.sub.1-7 alkoxy-C.sub.1-7 alkyl, hydroxy-C.sub.1-7 alkoxy-C.sub.1-7 alkyl, halogen or azaspirocycloalkyl, azabicyloalkyl, C.sub.2-7 alkynyl optionally substituted by NR'R'', or heteroaryl optionally substituted by C.sub.1-7 alkyl,
"R.sup.3 is halogen, C.sub.1-7 alkyl,
"R' and R'' are independently selected from hydrogen, C.sub.1-7 alkyl, hydroxy-C.sub.1-7 alkyl.
"In a particular embodiment, the FoxM1 splicing modifier for use in the prophylaxis or treatment of cancer is a compound of formula (I), wherein R.sup.1 is aryl or heteroaryl both substituents optionally substituted by C.sub.1-7 alkyl, C.sub.1-7 haloalkyl, halogen, C.sub.1-7 alkoxy, NR'R'', R.sup.2 is heteroaryl or heterocycloalkyl both substituents optionally substituted by C.sub.1-7 alkyl, hydroxy-C.sub.1-7 alkyl, halo-C.sub.1-7 alkyl, R.sup.3 is C.sub.1-7 alkyl.
"In a particular embodiment the invention relates to compounds of formula (I), wherein:
"R.sup.1 is phenyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 1,3-benzoxazolyl, indazolyl.
"In a particular embodiment, the FoxM1 splicing modifier for use in the prophylaxis or treatment of cancer is a compound of formula (I), wherein R.sup.2 is piperidinyl, morpholinyl, piperazinyl, pyridinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolidinyl.
"The present invention further provides the use of a compound of the present invention for the preparation of a medicament for the prophylaxis or treatment or of cancer.
"In a further aspect the present invention provides a pharmaceutical formulation comprising a compound of the present invention.
"In a further aspect the present invention provides a method for the prophylaxis or treatment of cancer comprising administering an effective amount of a compound of the present invention to a subject in need thereof.
"In a further aspect the present invention provides a method of screening for compounds for the prophylaxis or treatment of cancer comprising: a) contacting proliferating cells expressing the FoxM1 gene with a test compound, b) measuring the FoxM1 variant FoxM1A in the cells of step a), wherein an increased level of the FoxM1A variant compared to a control is indicative for a compound for the prophylaxis or treatment of cancer.
"In a further aspect the present invention provides a method of screening for compounds for the prophylaxis or treatment of cancer comprising: a) contacting proliferating cells expressing the FoxM1 gene with a test compound, b) measuring the FoxM1 variant FoxM1B and/or variant FoxM1C in the cells of step a), wherein a decreased level of the variant FoxM1B and/or variant FoxM1C compared to a control is indicative for a compound for the prophylaxis or treatment of cancer.
"In a particular embodiment of the method of the present invention the cells are fibroblasts.
"In a particular embodiment of the method of the present invention the FoxM1 variants are measured on RNA level.
"In a particular embodiment of the method of the present invention the FoxM1 variants are measured on protein level."
For more information, see this patent application: Ebeling, Martin; Metzger, Friedrich; Sivaramakrishnan, Manaswini. Screening Method. Filed February 19, 2016 and posted August 31, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170241983%22.PGNR.&OS=DN/20170241983&RS=DN/20170241983
Keywords for this news article include: Pharmaceutical Companies, Cancer, Genetics, Oncology, DNA Research, Hoffmann-La Roche Inc., F. Hoffmann-LaRoche Ltd., Diagnostics and Screening.
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