Bcr-Abl tyrosine kinase (Breakpoint cluster region Abelson) is a constitutively activated cytoplasmic tyrosine kinase (TK) and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors.
In Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event; consequently, it is targeted by ABL-tyrosine kinase inhibitors (TKIs), the first of which to be identified was imatinib mesylate. There are now four newer TKIs, three so-called second-generation inhibitors and one third generation inhibitor, all of which are more potent than imatinib in in vitro assays. Since 2001, the Bcr-Abl inhibitor imatinib represents the first-line therapy for CML and also the second-generation Bcr-Abl inhibitor nilotinib and the dual BcrAbl/Src inhibitor dasatinib are now successfully used. Ponatinib, AP24534, by Ariad Pharmaceuticals Inc. has been approved by FDA for the treatment of resistant or imatinib-intolerant CML and Ph+ ALL patients, especially those harboring the T315I mutation. On September 2012, bosutinib received the approval by FDA and in 2013 it was approved also by European Medical Agency.
The search for Bcr-Abl inhibitors is very active. Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.
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Asciminib (ABL-001) is a potent and selective allosteric ABL1 inhibitor with IC50 of 0.25 nM in BCR–ABL1-transformed BaF3 cells; binds (Kd=0.5-0.8 nM) to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation; inhibits phosphorylation of both STAT5 (Tyr694; pSTAT5) and BCR–ABL1 (Tyr245; pBCR–ABL1), and shows selective activity against all BCR–ABL1 cell lines (IC50=1-20 nM); retains activity against mutated ABL-1 Thr315Ile at low nanomolar concentrations; active in vivo, moderate oral absorption.
CZC-8004 (CZC8004, Dianilinopyrimidine-01) is a pan-specific kinase inhibitor that binds to a broad range of tyrosine kinases, including ABL, BTK, FAK, FER, JAK1, SRC, SYK, TEC, TNK1, TYK2, and YES at low micromolar concentrations.
A potent and selective type-II kinase inhibitor of Bcr-Abl; inhibits wt Bcr-Abl/T315I Bcr-Abl (IC50< 5 nM) and Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays; displays in vivo efficacy against T315I-Bcr-Abl in xenograft mouse model.
Nilotinib monohydrochloride monohydrate
A potent, selective, orally available inhibitor of both native and mutant Bcr-Abl with IC50 of 20-80 nM; inhibits proliferation of Ba/F3 cells expressing G250E, E255K(V), F317L, M351T, F486S, M244V, L248R, Q252H, Y253H, E255K, E279K, E282D, V289S, and L348M Bcr-Abl mutants at <1 uM; also inhibits activated forms of PDGFR and c-Kit with IC50 of 30-200 nM; prolongs survival of mice with leukemia due to imatinib-resistant mutants of Bcr-Abl.
Lyn-IN-1 is a potent and selective dual Bcr-Abl/Lyn inhibitor.
A potent, orally bioavailable, dual Src/Abl kinase inhibitor with IC50 of 0.5, 0.4, 0.5 and <1 nM for Src, Lck, Yes and Bcr-Abl, respectively; exhibits two-log increased potency relative to imatinib and retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants; prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML.
DPH is a cell-permeable, small-molecule c-Abl kinase activator with pEC50 of 6.1(EC50=794 nM); binds to the myristoyl binding site, also stimulates in vitro c-Abl phosphorylation; induces both pY245 (pEC50=5.6) and pY412 c-Abl phosphorylation; dose dependently induces Crk-L pY207 in KG-1 cells; the first small-molecule tool compound for c-Abl activation.
GNF-2 is a potent, allosteric, non-ATP competitive Bcr-Abl inhibitor that shows exclusive antiproliferative activity toward Bcr-abl-transformed cells; causes growth inhibition of Bcr-Abl positive cell lines with IC50s of 273 nM (K562) and 268 nM (SUP-B15); inhibits mutant Bcr-Abl E255V, Y253H cell growth.
Bafetinib is a potent and selective dual Abl/Lyn tyrosine kinase inhibitor with IC50 of 5.9 nM and 198 nM, respectively; more potent and specific against Bcr-Abl than imatinib, also inhibits the phosphorylation of CrkL and ERK in BaF3/E255K cells; inhibits the phosphorylation of Bcr-Abl harboring the M244V, G250E, Q252H, Y253F, E255K, E255V, F317L, M351T, E355G, F359V, H396P, or F486S mutations, but does not inhibit the phosphorylation of the T315I mutant; prolonges the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl.
WP1130 (Degrasyn) is a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression (IC50=1.8 uM), also inhibits deubiquitinases and blocks autophagy; reduces leukemic versus normal hematopoietic colony formation and strongly inhibits colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis; suppresses the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells in vivo; acts as a partly selective DUB inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37, triggers aggresome formation and tumor cell apoptosis.
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