INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Abstract

IntroductionImatinib mesylate (Gleevec; imatinib [Glivec]; formerly STI571), a specific inhibitor of ABL tyrosine kinase, is efficacious in treating Philadelphia chromosome-positive (Ph ϩ ) leukemias such as chronic myeloid leukemia (CML) and Ph ϩ acute lymphoblastic leukemia (ALL). 1,2 Within a few years of its introduction to the clinic, imatinib mesylate had dramatically altered the first-line therapy for CML, because it was found that most patients with newly diagnosed CML in the chronic phase (CP) achieved durable responses when treated with imatinib mesylate. 3 However, a small percentage of these patients, as well as most patients with advanced-phase CML and Ph ϩ ALL, relapse on imatinib mesylate therapy. 2,4 Several mechanisms of refractoriness and relapse have been reported, including point mutations within the ABL kinase domain, amplification of the bcr-abl gene, overexpression of bcr-abl mRNA, [5][6][7][8] increased drug efflux via a process mediated by P-glycoprotein (P-gp), 9 and activation of the Src-family protein Lyn. [10][11][12] There has recently been an increase in the numbers of reported cases of isolated central nervous system (CNS) relapse in which mainly patients with CML-blast crisis (BC) and Ph ϩ ALL who continued to have complete cytogenetic responses (CCgR) developed an extramedullary BC in the CNS. [13][14][15][16][17][18][19][20][21][22] Leis et al 23 reported that isolated CNS relapse occurred in 5 (20.8%) of 24 patients whose protocols included imatinib mesylate treatment, whereas Pfeifer et al 24 reported that CNS leukemia developed in 13 (12.1%) of 107 patients with Ph ϩ ALL. Isolated CNS relapse may be due to a limited penetration of imatinib mesylate into the cerebrospinal fluid (CSF), because it has been shown that concentrations of imatinib mesylate in the CSF are 1 to 2 orders of magnitude lower than the corresponding plasma levels. [24][25][26][27] Brain endothelial cells are characterized by their barrier properties, including tight junctions and various selective transporters. One of the transporters in the BBB, P-gp, which is expressed at the luminal side of the endothelial cells of the capillaries in the brain, plays an important role in drug efflux from the brain. Preclinical in vitro and in vivo studies have shown that imatinib mesylate is a substrate for P-gp, so that P-gp limits the distribution of imatinib mesylate to the brain. 28,29 The CNS can thereby become a sanctuary site of relapse in patients who are on prolonged imatinib mesylate therapy.To overcome resistance to imatinib mesylate, we recently developed a specific dual BCR-ABL/Lyn inhibitor, , which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent than The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Materials and methods Reagents ...

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

“…or BcrAbl bearing the E255K (Ba/F3/E255K), T315I (Ba/F3/T315I) or the H396P mutation (Ba/F3/H396P). 7,8 Murine FLCs that were retrovirally transformed with the bcr-abl gene were previously described, according to the guidelines of the Melbourne Directorate Animal Ethics Committee. 22 INNO-406 was provided by Nippon Shinyaku (Kyoto, Japan).…”

“…Moreover, INNO-406 inhibits the TK activities of most of the imatinib-resistant-mutated Bcr-Abl proteins except T315I mutant. 7,8 However, it appears that a few leukemic cells often survive exposure to imatinib or second-generation Bcr-Abl inhibitors. 9,10 Indeed, mathematical modeling studies suggest that complete eradication of Bcr-Abl þ leukemic cells may require simultaneous targeting of other vital molecules.…”

New drugs in the therapy of multiple myeloma

“…INNO-406 is a is a 3-substituted benzamide derivative, is a dual-specificity ABL and LYN kinase inhibitor that is 25-55-times more potent than imatinib against ABL. 29 In addition, INNO-406 inhibited the in vitro growth of cells with different mutant forms of BCR-ABL oncoproteins, 30 but not with T315I. 29,30 INNO-406 inhibited kinases other than ABL including ABL-related gene ARG and FYN, but not PDGFRα/β, SRC, BLK or YES.…”

“…29 In addition, INNO-406 inhibited the in vitro growth of cells with different mutant forms of BCR-ABL oncoproteins, 30 but not with T315I. 29,30 INNO-406 inhibited kinases other than ABL including ABL-related gene ARG and FYN, but not PDGFRα/β, SRC, BLK or YES. Furthermore, INNO-406 potently inhibited LYN kinase (IC50 of 19 nM), which has been implicated in BCR-ABL independent resistance, 13 without affecting the phosphorylation of Src, Blk or Yes, therefore presenting a further potential in imatinib-resistant CML.…”

Chronic myeloid leukemia – some topical issues

“…Like dasatinib, it appears also to inhibit the Src family kinase Lyn. 38,39 Bosutinib (SKI-606) is a new inhibitor that resembles dasatinib in activity against Abl, Src and Src family kinases. 40 Both agents are active against IM resistant mutant subclones other than the T315I.…”