Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

1. Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
Authors
Liu G¹
Abraham S¹
Liu X¹
Xu S¹
Holladay MW¹
(5 authors)
2. Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
Authors
Rooks AM²
Nepomuceno R²
Dao A²
Brigham D²
Belli B²
Armstrong RC²
(6 authors)
3. DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
Authors
Gitnick D³
Insko DE³
Gardner MF³
Christopher R³
(4 authors)
4. Technology Development, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
Authors
Zarrinkar PP⁴
(1 author)

Bioorganic & Medicinal Chemistry Letters, 14 Jul 2015, 25(17):3436-3441
https://doi.org/10.1016/j.bmcl.2015.07.023 PMID: 26208887

Abstract

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Full text links

Read article at publisher's site: https://doi.org/10.1016/j.bmcl.2015.07.023

References

Articles referenced by this article (15)

The roles of FLT3 in hematopoiesis and leukemia.
Gilliland DG, Griffin JD
Blood, (5):1532-1542 2002
MED: 12176867
Prognostic significance of FLT3 ITD and D835 mutations in AML patients.
Sheikhha MH, Awan A, Tobal K, Liu Yin JA
Hematol J, (1):41-46 2003
MED: 12692519
FLT3 as a therapeutic target in AML: still challenging after all these years.
Kindler T, Lipka DB, Fischer T
Blood, (24):5089-5102 2010
MED: 20705759
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).
Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS
Blood, (14):2984-2992 2009
MED: 19654408
Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor.
Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, Bhagwat SS
J Med Chem, (23):7808-7816 2009
MED: 19754199
Title not supplied
Cortes
J. Clin. Oncol. 2013
Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220).
Zorn JA, Wang Q, Fujimura E, Barros T, Kuriyan J
PLoS One, (4):e0121177 2015
MED: 25837374
Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.
Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP
Nature, (7397):260-263 2012
MED: 22504184
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R; Cancer Genome Project
Cell, (6):855-867 2004
MED: 15035987
A small molecule-kinase interaction map for clinical kinase inhibitors.
Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, [...] Lockhart DJ
Nat Biotechnol, (3):329-336 2005
MED: 15711537

Show 5 more references (10 of 15)

Citations & impact

Impact metrics

Citations

Jump to Citations

Alternative metrics

Altmetric item for https://www.altmetric.com/details/35585103

Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/35585103

Article citations

Silver-catalyzed direct conversion of epoxides into cyclopropanes using N-triftosylhydrazones.
Li L, Sivaguru P, Wei D, Liu M, Zhu Q, Dong S, Casali E, Li N, Zanoni G, Bi X
Nat Commun, 15(1):1951, 02 Mar 2024
Cited by: 0 articles | PMID: 38431716 | PMCID: PMC10908805
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC
Divergent Synthesis of Cyclopropane-Containing Lead-Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide.
Chawner SJ, Cases-Thomas MJ, Bull JA
European J Org Chem, 2017(34):5015-5024, 11 Sep 2017
Cited by: 6 articles | PMID: 28983191 | PMCID: PMC5601191
This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Search life-sciences literature (45,103,589 articles, preprints and more)

Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

Affiliations

Authors

Authors

Authors

Authors

Abstract

Full text links

References

The roles of FLT3 in hematopoiesis and leukemia.

Prognostic significance of FLT3 ITD and D835 mutations in AML patients.

FLT3 as a therapeutic target in AML: still challenging after all these years.

AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor.

Title not supplied

Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220).

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.

Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.

A small molecule-kinase interaction map for clinical kinase inhibitors.

Citations & impact

Impact metrics

Alternative metrics

Article citations

Silver-catalyzed direct conversion of epoxides into cyclopropanes using N-triftosylhydrazones.

Divergent Synthesis of Cyclopropane-Containing Lead-Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide.

Similar Articles

Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

3-Phenyl-1H-5-pyrazolylamine-based derivatives as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations.

The role of quizartinib in the treatment of acute myeloid leukemia.

Partnerships & funding

Similar Articles

Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).
Bioorg Med Chem, 21(11):2856-2867, 06 Apr 2013

3-Phenyl-1H-5-pyrazolylamine-based derivatives as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).
Bioorg Med Chem Lett, 22(14):4654-4659, 07 Jun 2012

Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations.
Eur J Med Chem, 100:151-161, 09 May 2015

The role of quizartinib in the treatment of acute myeloid leukemia.
Expert Opin Investig Drugs, 22(12):1659-1669, 26 Sep 2013

Search life-sciences literature (45,103,589 articles, preprints and more)

Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

Author information

Affiliations

Authors

Authors

Authors

Authors

Abstract

Full text links

References

Title not supplied

Citations & impact

Impact metrics

Alternative metrics

Article citations

Similar Articles

Partnerships & funding