PROUS SCIENCE INTEGRITY. Leukemia Therapy: Bcr-Abl Kinase Inhibitors: Selective vs Nonselective

Transcription

1 PROUS SCIENCE INTEGRITY Leukemia Therapy: Bcr-Abl Kinase Inhibitors: Selective vs Nonselective

2 SUMMARY In this use case, active compounds for Leukemia will be found and filtered by mechanisms of action and organization. Comparing two launched products for this condition, Gleevec and Tasigna, a structure search will be run to find structure-activity relationships for specific Bcr-Abl kinase inhibitors. From specific Abl kinase inhibitors list, related targets associated to these drugs will be examined and the targetscape for Acute Myeloiod Leukemia will be explored

3 LEUKEMIA Leukemia is a malignant disease of the bone marrow and blood that is characterized by the uncontrolled accumulation of white blood cells About 4,400 people in the U.S. will die of Chronic lymphocytic leukemia during 2009, according to the American Cancer Society. Among patients with Acute lymphocytic leukemia in the U.S., approximately 1,400 are predicted to die during the same year; two-thirds of these would be adults. Approximately 470 people with Chronic myelogenous leukemia and 9,000 with Acute myelogenous leukemia are expected to die as a cause of their disease this year in the U.S. The treatment of leukemia is complex and is based on a range of factors including characteristics of the disease itself (type of leukemia, extent of disease, whether or not the disease has been treated previously) and patient characteristics (age, symptoms and general health). Chemotherapy is the primary treatment for acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL), although the specific drugs used to treat each form differ. In some cases radiotherapy or stem cell transplantation may be used in combination with chemotherapy.

4 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Go to the Drugs & Biologics Knowledge Area from the pull down menu at the left part of the home page of Integrity

5 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Click the down arrow to open the pull-down of search fields and select Development Status -> Condition in this example.

6 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Next open the Browse Index of search terms for the search field chosen, run a preliminary lookup search to locate a term in the index, and then click the term on the right to copy it to the Search Form.

7 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Add other relevant criteria to the Search Form in this example, select Development Status -> Under Active Development = Y Click Start or hit return to launch the search.

8 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH From the list of active development programs for leukemia, retrieve the corresponding products by selecting the Product List from the Options pulldown menu

9 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Use the Filter by Statistics charts to further limit the search. From the Product List obtained, filter by Organization

10 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Check the companies of interest and click View Subset(s) In this example, select the Novartis and Novartis Oncology checkboxes

11 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH Select the Full Record option from the Options pull-down menu

12 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH The product record for Imatinib mesylate shows that it acts on multiple targets, including Abl Kinase and Bcr- Abl Kinase

13 DRUGS & BIOLOGICS KNOWLEDGE AREA: GUIDED SEARCH The product record for Nilotinib Hydrochloride Monohydrate shows that it acts selectively on Bcr- Abl Kinase. To further investigate selectivity of similar compounds a substructure search can be run.

14 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH To set up a structure search, select a Knowledge Area Drugs & Biologics in this example and click the Structure Search button to go to the Structure Search Form.

15 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH Draw or paste a structure in the structure search window.

16 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH Combine a substructure search with a text search by opening the search field menu and selecting a field - in this example, Therapeutic Group. Then open the Then open the corresponding Browse Index to select a term.

17 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH Use the Lookup box in the Browse Index to locate terms in the hierarchical Therapeutic Group index. Then click a term -- Oncolytic Drugs in this example -- to copy it to the Search Form.

18 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH Click Start or press Return to launch a search for products with this Therapeutic Group classification and that share a similar substructure.

19 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH Compounds can be classified quickly and easily by using Filter by Statistics. In this example, select to filter by Molecular Mechanisms.

20 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH The chart shows that many of the compounds have more than one mechanism of action. Using the checkbox function, select Bcr-Abl Kinase Inhibitors and click View Subset(s) to view the subset of compounds with this mechanism.

21 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH From the original list of product records retrieved that are Oncolytic Drugs and that have a similar structure, these are the compounds that are Bcr-Abl kinase inhibitors. Select the Product List with Structures from the pull-down menu

22 DRUGS & BIOLOGICS KNOWLEDGE AREA: STRUCTURE SEARCH From this list, structure-activity relationships can be examined. Access to Experimental Pharmacology, Pharmacokinetics/ Metabolism and other data can be obtained through the All Related Information via Quick Search

23 INFORMATION RETRIEVAL VIA TARGETS & PATHWAYS Select the Targets & Pathways enabled bar

24 INFORMATION RETRIEVAL VIA TARGETS & PATHWAYS From the Targets & Pathways list obtained, select the Targetscapes option

25 INFORMATION RETRIEVAL VIA TARGETS & PATHWAYS Click on the Acute Myeloid Leukemia Targescape

26 INFORMATION RETRIEVAL VIA TARGETS & PATHWAYS to view the molecular landscape for this condition.

27 SUPPORT/HELP For questions about Integrity s contents or features, send a message via the Help Request / Suggestion Form in Integrity or contact