Cancer is one of the top 10 causes of death in Taiwan. Protein kinases are often overexpressed in tumor cells. Due to this, they can be targeted for anti-cancer therapy. This project will focus on developing novel JAK2 and CDK7 inhibitors. The former generates mutations in nearly 50% of patients with Philadelphia chromosome-negative myeloproliferative disorder. Overexpression of JAK2 is also correlated with a variety of solid tumors. The latter is overexpressed in a large number of cancers. Currently, only two CDK7 inhibitors have entered phase I clinical trial. Therefore, targeting these kinases may provide novel cancer treatments. Although 39 kinase drugs have been approved, most of them are promiscuous drugs that affect unexpected kinases and exhibit drug resistance. For example, the JAK2 inhibitor, Renolitinib, which is used to treat myeloproliferative disorders, was tested in 439 kinase assays and found to inhibit 107 (~24%) different kinases. This leads to unexpected side effects. In addition, there are many cancer related protein kinases that have not been selectively targeted. Therefore, analyzing characteristics of kinase binding sites will allow for designs of highly specific and novel inhibitors, which may have high efficacy for cancer treatment. The main objectives of this project are as follows: (1) to establish computational models of oncogenic protein kinases for screening and designing novel drugs. The major targets in this project are JAK2 and CDK7. We will also identify and design inhibitors for other cancer-relevant kinases; (2) Designing and synthesizing hit-to-lead inhibitors using computational models; (3) studying the pharmacology, pharmacodynamics, mechanics, pharmacokinetics, and toxicology of designed compounds. Our team has achieved positive results in drug development by accomplishing the following: (1) development of drug design tools including iGEMDOCK and SiMMap for drug design and optimization; (2) identification of 78 novel inhibitors that target protein kinases, HDAC, and 20 other targets, nine of which show nanomolar activity; (3) a comprehensive team consists of investigators from multidisciplinary fields, including computational drug design, compound synthesis, pharmacology and toxicology. We also collaborate with the U.S. National Institute of Health for toxicology prediction and analysis. Our team has developed novel JAK2 and CDK7 inhibitors and will optimize the potency of identified inhibitors. JAK2 inhibitor, 711-J-001 (IC50: <10μM), is a highly selective towards JAK2 and JAK3 when tested in 97 kinase assays. We have also identified 8 derivatives, which showed more effective inhibitions. The derivatives can effectively inhibit the growth of cancer cells (GI50: 1 ~ 3 μM). Moreover, one of the compounds can inhibit the survival of blood cancer cell lines (IC50: 0.8 μM). A potential inhibitor have been developed for CDK7 that have been shown to inhibit the growth of cancer cell line (GI50: 3.8 μM). In the future, relevant derivatives will be designed based on their SiMMap models to improve activity and selectivity. We believe that our team will work diligently to screen for highly specific and effective cancer drugs that will improve the patient quality of life during treatment. Two hit-to-lead medications are expected to be completed in the three-year plan.
|Effective start/end date||8/1/18 → 7/1/19|
- drug design
- protein kinase inhibitors
- selective inhibitors
- molecular docking