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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.

 

References:

1. Soverini S, et al. Cancer. 2014 Apr 1;120(7):1002-9.

2. Thomas X, et al. Expert Opin Drug Discov. 2016 Nov;11(11):1061-1070.

3. Boer JM, et al. Eur J Cancer. 2017 Sep;82:203-218.

4. Shami PJ, et al. Leukemia. 2012 Feb;26(2):214-24.

5. Wylie AA,et al. Nature. 2017 Mar 30;543(7647):733-737.

 

Cat. No. Product Name CAS No. Information
PC-43444

WP1130

856243-80-6 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.
PC-43334

DCC-2036

1020172-07-9 DCC-2036 (Rebastinib) is a highly potent, non-ATP-competitive BCR-ABL1 inhibitor with IC50 of 0.8 and 4 nM for native ABL1 and gatekeeper mutant ABL1 T315I, respectively; also inhibits the SRC family kinases SRC, LYN, FGR, and HCK, and the receptor TKs KDR, FLT3, and TIE2 (IC50s=2-40 nM), but spares c-KIT (IC50=480 nM); potently inhibits unphosphorylated and phosphorylated of ABL1 native with IC50 of 0.75 and 2 nM, potently inhibits unphosphorylated and phosphorylated of ABL1 T315I with IC50 of 5 and 4 nM, also potently inhibits ABL1 H396P (IC50=1.4 nM); inhibits cellular proliferation of Ba/F3 cells expressing native or T315I mutant with IC50 of 5.4 and 13 nM, also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T with IC50 of 6-150 nM; prolongs survival in mouse Ba/F3 cell allograft models.

Blood Cancer

Phase 2 Clinical

PC-42862

Ponatinib

943319-70-8 Ponatinib (AP 24534) is a potent, orally active pan-inhibitor of BCR-ABL kinase with IC50 of 0.37 and 2.0 nM for ABL and mutant ABLT315I, respectively; retains high potency against other ABL mutants Q252H, Y253F, M351T and H396P (IC50s<0.5 nM), also inhibits c-Src, Lyn, c-KIT, VEGFR2, FGFR1, PDGFRα (IC50s=0.2-5 nM); inhibits the growth of cells expressing native or mutant BCR-ABL (IC50s=0.5–36 nM) suppresses BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens.

Blood Cancer

Approved

PC-42854

Lyn-IN-1

887650-05-7 Lyn-IN-1 is a potent and selective dual Bcr-Abl/Lyn inhibitor.
PC-63026

CHMFL-ABL-053

1808287-83-3 CHMFL-ABL-053 is a potent, selective and orally available Bcr-Abl/Src/p38 kinase inhibitor with IC50 of 70/62/90 nM; no inhibitory activity against c-Kit (>10 uM); inhibits the proliferation of CML cell lines K562 (GI50=14 nM), KU812 (GI50=25 nM), and MEG-01 (GI50=16 nM); completely suppresses tumor progression in the K562 cells inoculated xenograft mouse model with 50 mg/kg/day dosage treatment.
PC-62850

ABL-IN-29

1430719-97-3 ABL-IN-29 is a picomolar ABL kinase inhibitor with IC50 of 0.06/0.11 nM for wt ABL and ABL T315I respectively.
PC-62147

Asciminib

1492952-76-7 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.

Blood Cancer

Phase 3 Clinical

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