By a News Reporter-Staff News Editor at Clinical Trials Week A patent application by the inventor Lin, Jung-Yaw (Taipei City, TW), filed on May 2, 2016, was made available online on November 9, 2017, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also National Taiwan Normal University).
This patent application is assigned to National Taiwan Normal University.
The following quote was obtained by the news editors from the background information supplied by the inventors: "The present invention relates to pharmaceutical compositions and uses thereof, and more particularly, to a pharmaceutical composition for treating hepatocellular carcinoma and use thereof.
"Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer-related deaths. Although the prognosis of HCC is poor, surgical resection and liver transplantation often have curative effects in patients.
"Cancer cell migration is a critical process in tumor development and metastasis, and thus, anti-migration therapy is considered to be one of the approaches for cancer treatment. VEGF receptor signaling, such as VEGFR2 (KDR) signaling, has been implicated in HCC migration. The activation of downstream kinase, such as Src, FAK, and Rho-GTPase, induced by phosphorylated VEGFR2 results in remodeling of actin filaments and induction of migratory activity of tumor cells [1-4]. Previous studies have shown that knockdown of VEGFR suppresses HCC cell migration. The inhibition of VEGFR2 has been proposed as a novel therapeutic strategy for HCC patients. Various VEGFR2 kinase inhibitors such as sorafenib, sunitinib, and linifanib were developed and used in clinical trials.
"Previous studies have discussed the pharmacophore modeling of different VEGFR2 inhibitors . These inhibitors could be divided in two types, sunitinib-like or sorafenib-like, depending on the interacting hydrogen bonds. Sunitinib-like inhibitors form hydrogen bonds with residues of Asp1044, Cys917, and Asn921 near the protein surface. Sorafenib-like inhibitors interact with Asp1044, Cys917, and Glu883.
"Recently, anti-HCC therapy with sorafenib has been approved by FDA [6, 7]. Sorafenib is a tyrosine kinase inhibitor and the mechanism thereof is to inhibit the activity of Raf protein in cell, and then to block RAF/MEK/ERK signaling pathway and to inhibit kinases of cell surface, which results in cell death and inhibits angiogenesis. However, there still exists some common side effects of the sorafenib formulation as chemotherapy, for example hand-foot syndrome, skin rash, hair loss, itching, redness, hypophosphatemia, weight loss, diarrhea, abdominal pain, nausea, vomiting, gastrointestinal bleeding, anemia, lymphocyte count decreased, thrombocytopenia, neutropenia, sensory neuropathy, tiredness, difficulty with breathing, pulmonary hemorrhage, pain and so on.
"As known from the above, the therapies for HCC are quite limited. The conventional anticancer medicaments may affect the other functions of the subjects. Therefore, an efficient therapy for inhibiting HCC with decreased side effects which affect normal function is urged."
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventor's summary information for this patent application: "In view of the above-described issues, the present invention provides a pharmaceutical composition comprising a therapeutically amount of compound represented by formula (1):
"wherein R.sub.1 is H, hydroxy or methyl;
"R.sub.2 is H, C.sub.1-C.sub.3alkyl, hydroxy, CN or halogen;
"each of R.sub.3 and R.sub.4 is independently selected from the group consisting of H, C.sub.1-C.sub.3alkyl, hydroxy, CN, and halogen;
"R.sub.5 is H, hydroxy or methyl;
"R.sub.6 is H, C.sub.1-C.sub.3alkyl, hydroxy, CN, halogen, or COOR.sub.11; and
"R.sub.7 is C.sub.1-C.sub.3alkyl or COOR.sub.11, wherein R.sub.11 is H or C.sub.1-C.sub.3alkyl;
"at least an anticancer agent, wherein the molar ratio of the compound and the at least an anticancer agent in the pharmaceutical composition is from 2:1 to 1:32; and
"a pharmaceutically acceptable carrier.
"In one embodiment, the compound represented by formula (1) is a compound represented by formula (2) (also referred to corosolic acid (CA) hereinafter):
"In one embodiment, the pharmaceutical composition of the present invention further comprises at least an anticancer agent in a therapeutically efficient amount, and the anticancer agent is multikinase inhibitor.
"In one embodiment, the concentration of the compound represented by formula (1) is from 1 .mu.M to 50 .mu.M and the concentration of the at least an anticancer agent is from 1 .mu.M to 10 .mu.M. In one embodiment, the molar ratio of the compound represented by formula (1) and the at least an anticancer agent in the pharmaceutical composition is from 2:1 to 1:32.
"The present invention further provides a use of a compound represented by formula (1) for the manufacture of a medicament for treating hepatocellular carcinoma and/or inhibiting proliferation or migration of hepatocellular carcinoma cells. In one embodiment, the medicament inhibits VEGFR2 kinase, VEGFR2/Src/FAK/cdc42 pathway and actin remodeling.
"In one embodiment, the therapeutically efficient amount of the medicament administrated to a subject is from 2.5 mg to 5 mg of the compound per kilogram of body weight.
"In another embodiment, the therapeutically efficient amount of the medicament administrated to a subject such as human is from 0.2 mg to 0.42 mg of the compound per kilogram of body weight.
"In one embodiment, the medicament comprises at least an anticancer agent, wherein the medicament administered to a subject is from 12.5 mg to 25 mg per kilogram of bodyweight, and the therapeutically efficient amount of the at least an anticancer agent is from 10 mg to 20 mg per kilogram of bodyweight.
"The present invention further provides a use of a compound represented by formula (2) for the manufacture of a medicament for treating hepatocellular carcinoma and/or inhibiting proliferation or migration of hepatocellular carcinoma cells,
"wherein, the medicament further comprises at least an anticancer agent, and the molar ratio of the compound represented by formula (2) and the at least an anticancer agent is from 2:1 to 1:32 in the medicament.
"The pharmaceutical composition provided by the present invention can treat HCC efficiently and can inhibit the kinase activity in HCC cells and the actin activity therein, and thereby to inhibit proliferation and migration of HCC cells."
URL and more information on this patent application, see: Lin, Jung-Yaw. Pharmaceutical Composition and Use Thereof. Filed May 2, 2016 and posted November 9, 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=%2220170312234%22.PGNR.&OS=DN/20170312234&RS=DN/20170312234
Keywords for this news article include: Antineoplastics, Oncology, Sunitinib, Carcinomas, Liver Cancer, Therapeutics, Cancer Therapy, Sorafenib Therapy, Drugs and Therapies, Enzymes and Coenzymes, Multikinase Inhibitors, VEGF - VEGFR Inhibitors, Tyrosine Kinase Inhibitors, National Taiwan Normal University.
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