Drug Targets for Leukemia

Drug Targets for Leukemia Cancer

Drug targets for Leukemia cancer: pharmacology information

Drug targets for Leukemia cancer: bioreagents

Drug Targets BCR-ABL for Leukemia Cancer with Approved Drugs

Drug targets Cancer drugs Company
BCR-ABL imatinib Novartis
BCR-ABL dasatinib Bristol-Myers Squibb
BCR-ABL nilotinib Novartis
BCR-ABL bosutinib Pfizer
BCR-ABL ponatinib ARIAD Pharmaceuticals
BCR-ABL dasatinib Bristol-Myers Squibb

The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with chronic myelogenous leukemia.
The Abl protein shuttles between the nucleus and the cytoplasm; however, the Bcr-Abl oncoprotein remains in the cytoplasm, and the actual signal transduction pathway or pathways that the oncoprotein uses to alter gene expression and cause the phenotype of CML remain poorly defined. The juxtaposition of Bcr with Abl constitutively activates Abl tyrosine kinase by promoting dimerization or tetramerization of the fusion molecule; this, in turn, facilitates autophosphorylation, resulting in an increase in phosphotyrosine residues on Bcr-Abl itself, which creates binding sites for the SH2 domains of other proteins. A variety of such substrates, which can be phosphorylated on tyrosine residues, have been identified. (Goldman J M, Melo J V. BCR-ABL in chronic myelogenous leukemia–how does it work?[J]. Acta haematologica, 2008, 119(4): 212-217.)

Drug Targets CD52 for Leukemia Cancer with Approved Drugs

Drug targets Cancer drugs Company
CD52 alemtuzumab Genzyme Corporation

Ecotropic viral integration site 1 (EVI1) is an oncogenic transcription factor in human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. Because a high expression of EVI1 protein in acute myeloid leukemia cells predicts resistance to chemotherapy with a poor outcome, scientists have searched for molecular targets that will treat these patients with acute myeloid leukemia. In this study, It was determined that CD52, which is mainly expressed on lymphocytes, is highly expressed in most cases of acute myeloid leukemia with a high EVI1 expression (EVI1High). CAMPATH-1H, a humanized monoclonal antibody against CD52, has been used to prevent graft-versus-host disease and treat CD52-positive lymphoproliferative disorders. It was also investigated the antitumor effect of CAMPATH-1H on EVI1High acute myeloid leukemia cells. CAMPATH-1H significantly inhibited cell growth and induced apoptosis in CD52-positive EVI1High leukemia cells. Furthermore, CAMPATH-1H induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against CD52-positive EVI1High leukemia cells.

Drug Targets CD20 for Leukemia Cancer with Approved Drugs

Drug target Cancer drugs Company
CD20 Rituximab IDEC Pharmaceuticals
CD20 Ofatumumab GlaxoSmithKline

CD20 is a cell surface protein expressed on B cells at most stages of development. However, CD20 is only weakly expressed on the surface of chronic lymphocytic leukemia cells. CD20, which contains both an N and C terminus within the cell, is a member of the MS4A protein group. CD20 is comprised of two extracellular loops, of which the larger component is made up of 44 amino acids. Rituximab was the first mouse–human chimeric antibody clinically developed to target CD20 and acts through multiple different mechanisms, including complement-mediated cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and direct toxicity. Rituximab binds to the larger extracellular loop of CD20. It has been shown that rituximab specifically recognizes epitopes containing the two amino acids alanine and proline, which facilitate its binding. The use of adjunctive rituximab with chemotherapy as opposed to rituximab monotherapy has been shown to modestly improve both OS and PFS in chronic lymphocytic leukemia patients, especially those who are more fit. (Nahas M R, Arnason J E. Targeting CD20 in chronic lymphocytic leukemia[J]. Blood Lymphatic Cancer: Targets Therapy, 2015, 5: 43-53.)

Drug Targets BTK for Leukemia Cancer with Approved Drugs

Drug target Cancer drugs Company
BTK Ibrutinib Janssen Pharmaceuticals, Inc.

BTK is a critical mediator of B-lymphocyte signaling and development. BTK is also a critical mediator in B-cell signaling. It is apparent that BTK is critical for the development and function of normal B lymphocytes, and protein expression appears to be required for chronic lymphocytic leukemia development. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of chronic lymphocytic leukemia, demonstrating that BTK is a critical kinase for chronic lymphocytic leukemia development and expansion and thus an important target of ibrutinib. This demonstrates the importance of BTK in the therapy of chronic lymphocytic leukemia. (Woyach JA, Bojnik E, Ruppert AS, et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207-1213. doi:10.1182/blood-2013-07-515361.)

Drug Targets PI3Kδ for Leukemia Cancer with Approved Drugs

Drug target Cancer drugs Company
PI3Kδ Idelalisib Gilead Sciences, Inc.

Idelalisib (GS-1101, CAL-101, 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one) is a potent small-molecule inhibitor that is highly specific for PI3Kδ. In lymphoid cell lines and primary patient samples, idelalisib abrogates PI3K/Akt signaling and promotes apoptosis. Phase 1a testing in healthy volunteers established idelalisib oral bioavailability and safety at dose levels that achieve plasma concentrations shown to inhibit PI3Kδ in preclinical models. Another study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib for chronic lymphocytic leukemia.

Drug Targets BCL-2 for Leukemia Cancer with Approved Drugs

Drug target Cancer drugs Company
BCL-2 Idelalisib Gilead Sciences, Inc.

BCL2 protein family plays an important role in regulating the cellular program of apoptosis. Normal cellular homeostasis appears to be dependent on the balance between pro- and antiapoptotic members of BCL2 family. BCL2 is overexpressed in almost all types and subtypes of leukemia, indicating the importance of this molecule in disease pathogenesis and evolution. BCL2 is the most well studied member of the family, but evidence shows that other BCL2 related family proteins like BAX and MCL-1 are important as well. Expression levels of BCL2 and BCL2L12 were altered during apoptosis induced by widely used chemotherapeutic drugs in human leukemia cells. These molecules may not be used as disease markers in most cases, but their importance lies in (a) explaining drug chemoresistance and (b) in the effort to design new agents with a greater specificity. Further research should focus on the role of BCL2 family members in leukemogenesis. (Tzifi F, et al. The role of BCL2 family of apoptosis regulator proteins in acute and chronic leukemias[J]. Advances in hematology, 2011, 2012.)

Drug targets for Leukemia cancer: Related Information