Disease Area, Oncology II
Product Name: ABT-869 (Linifanib) l KDR, CSF-1R, FLT1/3, PDGFRb inhibitor (#C2869)
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ABT-869 (Linifanib) is an aminobenzopyrazole-based, orally available, ATP-competitive receptor tyrosine
kinase inhibitor with IC50 potency against KDR, FLT1, CSF-1R, FLT3, and PDGFRb of 4 nM, 3 nM, 3 nM,
4 nM, and 66 nM, respectively. It is highly selective (> 1uM) against unrelated tyrosine kinases and
serine/threonine kinases. [1] In cellular assays, ABT-689 exhibited potency against ligand-induced
PDGFRbeat, KIT, and CSF-1R phosphorylation, with IC50s of 2, 31, and 10 nM, respectively.
In vivo, ABT-869 is orally effective in a wide range of human xenograft models, including MV4-11, HT1080,
H526, DLD-1, A431, MX-1, MDA-231, MDA-435LM, and glioma 9L. [2] ABT-869 displays antiproliferative and
apoptotic effects on cancer cells dependent on mutant kinases, such as FLT3. Consequently, ABT-869 is in
clinical studies for the treatment of acute myeloid leukemia (AML). [3, 4] ABT-689 has been shown to induce
apoptosis through an AKT and GSK-3beta-dependent pathway, thus suggesting that combination therapies
with GSK-3beta inhibitors may be a promising approach to AML treatment. [3]
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Details
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Chemical Formula:
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C21H18FN5O
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CAS No.:
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796967-16-3
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Molecular weight:
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375.41
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Purity:
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> 98%
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Appearance:
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White
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Chemical name:
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1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea
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Solubility:
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Up to 100 mM in DMSO
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Synonyms:
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ABT-869, ABT 869, ABT869, AL-39324, AL39324, Linifanib
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Storage:
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For longer shelf life, store solid powder at 4oC desiccated, or DMSO solution
at -20oC
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1. Albert et al., Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer
Ther. 2006, 5, 995-1006. Pubmed ID: 16648571
2. Zhou et al., ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. J.
Hematol. Oncol. 2009, 2, 33-45. Pubmed ID: 19642998
3. Hernandez-Davies et al., The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces
apoptosis through an Akt and glycogen synthase kinase 3?-dependent pathway. Mol. Cancer Ther.
2011, 10, 949-959. Pubmed ID: 21471285
4. Shankar et al., ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3
phosphorylation and signaling in acute myeloid leukemia. Blood, 2007, 109, 3400-3408.
Pubmed ID: 19642998
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Product Name: ABT-888 (Veliparib) l PARP1/2 inhibitor (#C2888)
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ABT-888 (Veliparib) is an orally-available, benzimidazole-based inhibitor of poly(ADP-ribose) polymerase
with Ki values of 5.2 and 2.9 nM, for PARP1 and PARP2, respectively. [1] ABT-888 exhibits activity in C41
whole cells at an EC50 of 2 nM [2], and inhibits PAR formation in cells at an EC50 of 4.5 nM. [3]
ABT-888 efficiently crosses the blood-brain barrier and has been shown to potentiate DNA-damaging agents
such as temozolomide, cisplatin, carboplatin, cyclophosphamide, irinotecan, and radiation. [1, 4] Treatment
with temozolomide in the S phase generated higher levels of double-stranded DNA breaks and general
higher levels of cytoxicity.
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Details
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Chemical Formula:
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C13H16N4O
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CAS No.:
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912444-00-9, 912445-05-7
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Molecular weight:
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244.29
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Purity:
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> 98%
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Appearance:
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White solid
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Chemical name:
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(R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide
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Solubility:
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Up to 75 mM in DMSO
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Synonyms:
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ABT-888, ABT 888, ABT888, Veliparib
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Storage:
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For longer shelf life, store solid powder at 4oC desiccated, or DMSO solution
at -20oC
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References
1. Palma et al., The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and
reduction in PARP activity in vivo. Anticancer Res. 2008, 28, 2625-2636. Pubmed ID: 19035287
2. Penning et al., Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-
2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J. Med. Chem. 2009, 52,
514-523. Pubmed ID: 19143569
3. Liu et al., Potentiation of temozolomide cytotoxicity by poly(ADP)ribose polymerase inhibitor ABT-888
requires a conversion of single-stranded DNA damages to double-stranded DNA breaks. Mol. Cancer Res.
2008, 6, 1621-1629. Pubmed ID: 18922977
4. Donawho et al., ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-
damaging agents in preclinical tumor models. Clin. Cancer Res. 2007, 13(9), 2728-2737.
Pubmed ID: 19143569
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Product Name: AC220 (Quizartinib) | FLT3 inhibitor (#C2222)
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AC220 (Quizartinib) is an orally-available, imidazobenzothiazole-based inhibitor of Flt3, with an in vitro Kd of
2 nM. In vitro cell studies show that AC220 has a IC50 of 0.5 nM for MV-411 cells. [1] In a variety of leukemic
cell lines, AC220 inhibited Flt3 phosphorylation of MV4-11, MOLM-14, SEM-K2, and RS4-11 at IC50s of 1, 2, 4,
and 4 nM, respectively. Furthermore, inhibition of cell proliferation on these same lines were measured as
0.3, 0.1, 0.4, and >10000 nM, respectively. [2]
In a KinomeScan panel of 402 kinases, AC220 has a high degree of specificity toward Flt3 with only mild
inhibition of closely related RTKs such as KIT, PDGFR, RET, VEGFR2. [3]
Ina Flt3-ITD acute myeloid leukemia mouse model, AC220 was shown to extend significantly the survival at 1
mg/kg QD dosing, and eradicates tumors in a Flt3-dependent mouse xenograft model at 10 mg/kg. [3]
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Details
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Chemical Formula:
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C29H32N6O4S
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CAS No.:
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950769-58-1
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Molecular weight:
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560.67
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Purity:
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> 98%
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Appearance:
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White solid
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Chemical name:
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Urea, N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-N'-[4-[7-[2-(4-morpholinyl)ethoxy]
imidazo[2,1-b]benzothiazol-2-yl]phenyl]-
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Solubility:
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Up to 100 mM in DMSO
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Synonyms:
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AC-220, AC220, Quizartinib
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Storage:
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For longer shelf life, store solid powder at 4oC desiccated, or DMSO solution
at -20oC
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References
1. Belli et al., AC220, a uniquely potent and selective FLT3 inhibitor, enhances the cytotoxiceffects of
chemotherapeutic agents in cell culture and in mouse tumor xenografts. Ambit Biosciences ASH Poster,
2009, Abstract 2052.
2. Gunawardane et al., INHIBITION OF FLT3 SIGNALING BOTH IN VITRO AND IN VIVO BY AC220, A SECOND
GENERATION POTENT AND SELECTIVE FLT3 INHIBITOR. Ambit Biosciences AACR Poster, 2010,
Abstract 3619.
3. Zarrinkar et al., AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute
myeloid leukemia (AML). Blood 2009, 114(14), 2984-2992. Pubmed ID: 19654408
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Product Name: ACY-1215 (Rocilinostat) | HDAC6/8 inhibitor (#C2121)
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ACY-1215 (Rocilinostat) is an orally-available, hydroxamic acid-based, selective inhibitor of HDAC6 and
HDAC8 with IC50 values of 5 nM and 100 nM, respectively. ACY-1215 is12-, 10-, and 11-fold less active
against HDAC1, HDAC2, and HDAC3, respecitvely, and has minimal activity (IC50 > 1 uM) against HDAC4,
HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1 and Sirtuin2. [1]
To demonstrate ACY-1215 selectivity for HDAC6, MM.1S cells were cultured with increasing doses of ACY-
1215 for 6 hours. Dose-dependent increased acetylated a-tubulin was observed at low doses (0.62 uM) with
no effect on histone acetylation.
ACY-1215 has been shown to work synergistically with bortezomib in multiple myeloma models.
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Details
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Chemical Formula:
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C24H27N5O3
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CAS No.:
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1316214-52-4
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Molecular weight:
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433.5
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Purity:
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> 98%
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Appearance:
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White solid
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Chemical name:
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2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide
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Solubility:
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Up to 100 mM in DMSO
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Synonyms:
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AC-1215, ACR1215, Rocilinostat
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Storage:
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For longer shelf life, store solid powder at 4oC desiccated, or DMSO solution
at -20oC
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References
1. Santo et al., Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6
inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012, 119, 2579-2589.
Pubmed ID: 22262760
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