Invention Name

C-Kit kinase inhibitor cancer drug candidate DBPR216

Inventor

Chiang Wei-tang, Shi Chuan, Tsai Hui-chen

Research Unit

Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes

Gastrointestinal stromal tumors are the most common gastrointestinal mesenchymal tumors and originate from interstitial cells of Cajal. Median years of occurrence is 60-65 years old. Worldwide incidence of 10-20 per one million people. 

Technology Abstract
The aminothiazole series of compounds are multi-targeted kinase inhibitors. The DBPR216 compound, which is representative of these, has a very good inhibiting effect and on drug resistant gastrointestinal stromal tumor (GIST) cell lines caused by c-Kit mutations, as well as acute myeloid leukemia (AML) cell lines from C-KIT and FLT3-ITD mutations, whether in or outside the body. 

Applications and Market Potential
Applications:
Cancer clinical treatments, most likely for GIST and AML. In addition, this aminothiazole series of compounds are multi-kinase inhibitors, and so it’s possible to apply them to solid tumors, giving them a broader application.
Market Potential:
Aminothiazole compounds could possible become a second-line drug for GIST, currently the second-line treatment for this cancer is Sunitinib, which has a global market value of around US$329 million in the treatment of GIST. The treatment of AML is mainly through chemotherapy (combined use of cytarabine and anthracycline) and stem cell transplant, the global market of AML in 2011 was US$239 million, and this is expected to reach US$731 million by 2018. In addition to the increase in incidence of AML, one of the main reasons for the predicted rapid growth in the AML treatment market is that innovative and high-priced AML drugs are expected to be granted market approval by the US Federal Drug Administration (FDA) in the future. Among AML sufferers, around 30% of cases are related to the FLT-ITD mutation, and with another 6% of sufferers, the onset of illness was related to c-KIT mutations. If FLT3/c-KIT inhibitors can be developed to treat AML, its market value could make up one third of the global AML market.  

Advantages compared to existing technology
In Vitro Activation
DBPR216’s ability to suppress the replication of GIST cell lines on which first-line drug Imatinib is ineffective, such as GIST430 and GIST48 cell lines, is ten to over one hundred times better than second-line drug Sunitinib and second-line drug Regorafenib
In Vivo Activation
GIST: In animal experiments on GIST430 xenografts on which second-line drug Sunitinib is effective, low dosages of DBPR216 (30mpk) are more effective against tumors than high dosages (80mpk) of Sunitinib.
AML: On AML cell lines, c-KIT mutation Kasumi-1 cell lines and FLT3-ITD mutation MOLM-13 cell lines, DBPR216 has shown a high rate of effectiveness in experiments, and can quickly reduce tumors and have a slowing effect on its entirety.

IPR Status
One US provisional application pending

Invention Name

Selective Sialtransferase Inhibitors Suppress Cancer Growth and Metastasis

Inventors

Li Wen-shan, Hung Wen-jun, Shen Chia-ning

Research Unit

Institute of Chemistry, Academia Sinica; National Institute of Cancer Research, National Health Research Institutes; Genomics Research Center, Academia Sinica

Technology Abstract
This invention discloses the selective sialtransferase inhibitor and other novel sialtranferase inhibitors which are effective in selectively regulating (suppressing) α2,3 and α2,6-N-linked glycans sialyiated proteins (non O-linked glycans proteins).

These selective sialyltransferase inhibitors were demonstrated to improve the water solubility properties, reduce toxicity, inhibit a variety of cancer cell migration and invasion, exhibit angiogenesis inhibition of human umbilical vein endothelial cell, and thereby suppresses tumor growth and metastasis.

Possible Fields of Application and Market Potential
New molecular targeted therapy for cancer
Reduction of side effects for chemotherapy patients

Advantages When Compared to Existing Technologies
1. There are no selective sialyltransferase inhibitors present in the drug market and literature. This invention provides an alternative treatment option of molecular targeted therapy for cancer patients who have an overexpression of the “sialyated N-linked glycoproteins” profiling!
2. The selective sialyltransferase inhibitors have a higher water solubility and lower toxicity than those of the conventional sialyltransferase inhibitors.
3. The existing molecular targeted cancer therapies do not include this technology. This invention is novel.
4. The selective sialyltransferase inhibitors have more effective therapeutic advantages (e.g., inhibition of tumor growth and delay of cancer metastasis) than those of the existing sialyltransferase inhibitors.

IPR Status
PCT and ROC patent application pending

Invention Name

Composition and method for modulating fibroblast growth factor receptor 3

Inventor

Chen Hsuan-chung, Li Yi-Ching, Wu,Jer-Yuarn, Kao Hsiao-rong

Research Unit

Institute of Cellular and Organismic Biology, Academia Sinica

Technical Abstract
Over-activation of FGFR3 causes human inherited skeletal dysplasia, and somatic mutation of FGFR3 causes cancer. Currently there is still no effective treatment to treat skeletal dysplasias caused by FGFR3 activating mutations. We’ve built a specific high-throughput screening system, to select plant extracts, to go further in purifying effective ingredients and isolating pure compounds which can inhibit FGFR3 activation. Effective ingredients have already been proven to improve skeletal development in mice with achondroplasia (ACH), and inhibit cancer cell growth due to activation of FGFR3. The purified effective parts, and pure compounds, can be developed as treatment for skeletal dysplasia and related cancers due to FGFR3 activation. 

Future Works

1. The therapeutic potential of the chemical in ACH mice
2. The therapeutic potential of the chemical compounds in FGFR3 activation cancers xenografted mouse models
3. The target specificity and molecular acting of the chemical compounds in inhibition of FGFR3.

IPR Status
US provisional application filed

Invention Name

A Small Molecule Inhibitor of ErbB2 Can Rescue the Cognitive Impairment of the APP/PS1 Transgenic Mice

Inventor

Liao Yong-feng, Wang Bo-chien

Research Unit

Institute of Cellular and Organismic Biology, Academia Sinica

Summary:
ErbB2-elicited signaling could govern the substrate selectivity/availability of γ-secretase, and potentially be a novel pharmacological target for Alzheimer’s Disease therapy.
- APP-C99, but not the psychological γ-secretase substrate Notch, could be preferentially degraded in autophagy elicited by the selective down-regulation of ErbB2.
- An irreversible ErbB1/2-selective dual inhibitor, CL-387.785, could specifically reduce γ-secretase-mediated production of Aβ without affecting Notch signaling.
- Oral administration of CL-387,785 significantly improves cognitive functions of APP/PS1 transgenic mice.
- Repurposing CL-387.785 as a novel therapeutic for AD
- Development of novel ErbB2-specific antagonists?
- Other RTK inhibitors???

Potential Application and Market Potential
Alzheimer’s disease treatment and prevention; Treatment and prevention of other related degenerative nerve diseases.

IPR Status
US provisional application filed

Invention Name

Thin Shell Polymeric Hollow Nanoparticles and Uses Thereof

Inventor

Hu Che-ming, Chen Hui-wen, Yao Bing-yu

Research Institute

Institute of Biomedical Sciences, Academia Sinica

Synthetic polymer nanoparticles have wide application across many fields, but the majority are solid inside, so can't be used as a container for soluble or macromolecule content. This hollow nanoparticle invention is a breakthrough in terms of the limits of normal nano particle technology, and acts as a container for soluble particles.

Possible Application and Market Potential
In 2004, nanopharmaceutical preparations reached the US$6.8 billion sales mark. Every year at least US$3.8 billion is spent on nanotechnology development for medicines and vaccines. The applications of nanoparticles are constantly expanding, in terms of drug delivery, disease diagnosis, and vaccine preparation. This invention can be used in various biological reagents and can improve the effectiveness of treatment, resulting in new preparations of drugs and vaccines. The diseases it can be applied to are cardiovascular disease, cancer, autoimmune diseases and infectious diseases, among others.

IPR Status
PCT and ROC patent application filed

Invention Name

Peripheral Cannabinoid Receptor 1 (CB1) and Type 2 Diabetes Mellitus - DBPR211

Inventor

Hsia Ke-shan, Chang Chun-ping, Chao Yu-sheng

Research Institute

Institute of Biotechnology and Pharmaceutical Research (IBPR), National Health Research Institutes

1. Potent and highly selective antagonist of peripheral CB1 receptor
2. Minimum penetration into brain with no central effects (supported by direct drug exposure measurement and 18F-labelled PET imaging studies) - does not compete with the centrally mediated CB1 agonist (CP55940)
3. Chronic treatment (oral administration) effectively ameliorates insulin resistance in db/db diabetic mice and DIO mice. Weight loss and reduction in hepatic steatosis in DIO mice was also observed.
4. Orally bioavailable with acceptable DMPK profile.
5. Can be readily scaled up with sound developable process (11 steps/ 6.5% yield in kilogram scale).
6. A novel and patentable lipid-based formulation has been successfully developed for GLP and phase I/II studies.
7. Potential First-in-Class asset for T2DM, obesity and non-alcoholic fatty liver disease.

IPR Status
Granted:
1 ROC patent, 1 US patent, 1 Canadian patent, 1 South African patent, 1 Japanese patent, 1 South Korean patent, 1 Chinese patent, 1 Australian patent, 1 Russian patent
Pending:
1 Indian patent, 1 United Arab Emirates patent, 1 European patent, 1 Brazilian patent

Invention Name

Identification of a novel antagonist-to-agonist allosteric modifier (AAM) of MOR: DBPR116

Inventor

Weng Shao-hua, Ye Hsiu-hua, Lin Shu-yu, Shi Chuan

Research Institute

Institute of Biotechnology and Pharmaceutical Research (IBPR), National Health Research Institutes

Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine -- activation of mu-opioid receptor (MOR), delta-opioid receptor (DOR) or kappa-opioid receptor (KOR). Disadvantages include respiratory depression, sedation, constipation, frequent nausea and vomiting, abuse/addiction potential; tolerance build-up.

1. Due to the novel mechanism of action of AAM, DBPR116 should be a potentially First-in-Class drug for treating severe pain.
2. DBPR116/naltrexone combination exerts good antinociceptive effect in mouse model of acute thermal pain, however, with fewer common side effects of opioids including analgesic tolerance, constipation, and decrease in heart rate.
3. DBPR116/naltrexone combination exhibits even better antinociceptive effect than morphine does in mouse models of neuropathic pain and cancer pain.
4. World chronic pain medication market: US$15-30 billion

IPR Status
Pending: 1 PCT application, 1 US patent, 1 ROC patent

Invention Name

5-methoxytryptophan: a novel predictive biomarker and a therapeutic agent for inflammatory diseases

Inventor

Kuo Cheng-chin,  Wu Kun-yu

Research Institute

Institute of Cellular and System Medicine, National Health Research Institutes

Introduction:
Abnormal activation of inflammatory signaling has been implicated in the development and progression of inflammatory diseases.
Objectives:
The identification of metabolites as an inflammatory signal modulator may provide basic and clinical knowledge to develop specific therapies against inflammatory diseases.

IPR Status
Granted: 1 ROC patent
Pending: 1 US patent, 1 Chinese patent, 1 European patent, 1 Canadian patent, 1 Australian patent, 1 New Zealand patent

Invention Name

Identification of Oncogenic Nonsense mutations of HBV S gene in HBV-related hepatocellular carcinoma

Inventor

Huang Hsiu-fen, Ye Chao-ting, Chen Ya-ting

Research Institute

Division of Molecular and Genome Medicine, National Health Research Institutes

HBV Mutations
During the course of chronic hepatitis B infection, mutations may occur through the genome . These mutations reflect the attempt of the virus to adjust itself to the host immunity.

HBV mutations

1. Lack proof-reading function
1. The daily rate of de novo HBV production may reach 1011 virions
2. The estimated mutation frequency is 1.4~3.2 x 10-5 nucleotides.
2. Escape mutants result from selection pressures:
1. endogenous: host immune clearance.
2. exogenous: vaccines, antivirals.

1. So far we have identified 11 HBV S gene truncation mutants (sL15*, sL21*, sS61*, sC69*, sL95*, sW156*, sW163*, sW172*, sW182*, sW196* and sL216*) in HBV-related HCCs, all except one (sL95*) belong to genotype C of HBV, which is quite interesting, since genotype C has been found to be one risk factor for the development of HBV-related HCC in Taiwan.
2. Among them, 6 different HBV S nonsense mutations have been studied and demonstrated to have transformation activities. It is possible that most of the S gene nonsense mutations had transformation activity. Thus, it is highly likely that such mutants played a role in the initiation stage of liver cancer cell transformation.

1. It is possible that most of the S gene nonsense mutations had transformation activity. Thus, it is highly likely that such mutants played a role in the initiation stage of liver cancer cell transformation.
2. However, judging from the persistence of this mutant in the cancerous tissue, it was possible that the mutant also contributed to maintenance of HCC tumor growth.
3. Furthermore, we discovered that 3 tumor tissues with sW182* had multiple S nonsense mutations, which might result in an additive effect to enhance their transformation ability.
4. The nonsense mutations of HBV S gene could be an important prediction factor for development of HCC in HBV patients, especially those with cirrhosis.

IPR Status
Granted: 1 US patent, 1 ROC patent
Pending: 1 Chinese patent and 1 South Korean patent

Invention Name

OptoP: a pioneering high content cell
image-registered protein labeling system defining precise protein identification

Inventor

Liao Chung-chi, Chen Yi-te, Chang Chi-wei, Chung Ying-wen

Research Institute

Institute of Atomic and Molecular Sciences, Academia Sinica

Summary:

1. HBcARD peptide had broad spectrum antimicrobial activity for Gram-positive and Gram-negative bacteria by diverse mechanisms.
2. Modified HBcARD peptides are more resistant to serum protease, and exhibit low toxicity and high efficacy in mouse sepsis and lung infection models in vivo.
3. A. baumannii is the number one noscomial infection in Taiwan, and among the top worldwide. Colistin is the last hope for treating Gram-negative bacteria. Our HBcARD peptide can kill colistin-resistant A. baumannii highly efficiently in vivo and in vitro.

IPR Status
US patent application pending, ROC patent pending

Invention Name

A novel antimicrobial peptide against drug-resistant bacteria

Inventor

Shih Chia-he, Chen Heng-li, Su Pei-yi

Research Institute

Institute of Biomedical Sciences, Academia Sinica

Antibiotics are the most commonly used drug to control bacterial infections globally.

However, over the past few decades, the extensive use of antibiotics has caused the rapid increase of drug resistance in both Gram-negative and Gram-positive bacteria. There are several life-threatening antibiotics-“ESKAPE” pathogens, which cause the majority of nosocomial infection, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. This urgent situation was headlined as “Bad bugs, No drugs” by The Infectious Diseases Society of America.

We identified a novel antimicrobial peptide (HBcARD) from human hepatitis B virus (HBV) core protein (HBc) arginine-rich domain (ARD). This peptide can bind to the LPS of gram-negative bacteria and the intracellular macromolecules of gram-positive bacteria (Figure 1). The minimal bactericidal concentrations (MBC) of HBcARD peptides against Gram positive and Gram negative bacteria generally fall in the range around 2 - 4 μM.

HBcARD can kill colistin-resistant clinical isolates of A. baumannii in vitro. The estimated therapeutic index in vitro is significantly larger than 100. In a sepsis mouse model, HBcARD peptide exhibited a potent protection effect against S. aureus.

Figure 1. Illustration of the mode of action (MOA) of HBcARD peptides. HBcARD can bind to LPS of Gram-negative bacteria and the intracellular macromolecules of Gram-positive bacteria.

IPR Status
ROC patent granted, US patent pending, Chinese patent pending, European patent pending

Invention Name

Targeting antigens to FcγR induces potent immune response

Inventor

Chen Hsin-wei, Leng Chi-hsiang, Liu Shih-jen

Research Institute

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes

Summary

1. OVA/F and OVA/FL fusion proteins possess the ability to bind to FcγRs.
2. OVA/F and OVA/FL fusion proteins induce robust immune responses without exogenous adjuvant formulation.

Applications

1. Viral vaccines: Fusion with viral antigens
2. Cancer vaccines: Fusion with tumor-associated antigens
3. Others: Fusion with interested antigens
4. Delivery system

IPR Status
US provisional patent pending