Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants

Weisberg, Ellen; Choi, Hwan Geun; Ray, Arghya; Barrett, Rosemary; Zhang, Jianming; Sim, Taebo; Zhou, Wenjun; Seeliger, Markus A.; Cameron, Michael D.; Azam, Mohammad; Fletcher, Jonathan A.; Dębiec‐Rychter, Maria; Mayeda, Mark; Moreno, Daisy; Kung, Andrew L.; Jänne, Pasi A.; Khosravi‐Far, Roya; Melo, Junia V.; Manley, Paul W.; Adamia, Sophia; Wu, Catherine J.; Gray, Nathanael S.; Griffin, James D.

doi:10.1182/blood-2009-11-251751

Cited by 62 publications

(54 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For this reason, current efforts are focused on the development of new drugs with ABL TKI activity against BCR-ABL mutants. 44 Dasatinib, a multitargeted kinase inhibitor with specificity for BCR-ABL, Src family kinases, and other TKs, has shown an advantage over classic ABL TKIs through binding to mutation-induced conformational dynamics of the ABL kinase domain. 45 Dasatinib shows significant antileukemic activity and is increasingly used in the treatment of BCR-ABL ϩ B-ALL.…”

Section: Discussionmentioning

confidence: 99%

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Chang

Sánchez-Aguilera

Shen

et al. 2012

Blood

View full text Add to dashboard Cite

Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL+ acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL–dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2–deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL–expressng acute lymphoblastic leukemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Chang

Sánchez-Aguilera

Shen

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…We previously reported the first (to our knowledge) covalent FGFR irreversible inhibitor (FIIN-1), which targets a cysteine residue conserved in all four FGFR kinases and which inhibits the proliferation of Ba/F3 cells engineered to be dependent on FGFR1, FGFR2, or FGFR3 with EC 50 s in the 10-nM range, a potency comparable to that exhibited by BGJ398 and AZD4547 (43). All FGFR kinases have a valine at the gatekeeper position, in contrast to ABL, EGFR, KIT, and PDGFR, which all possess a threonine gatekeeper in which resistance can be conferred by mutation of the threonine to a larger hydrophobic valine, isoleucine, or methionine residue in response to first-generation inhibitors of these kinases (44)(45)(46).…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

132

View full text Add to dashboard Cite

The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

show abstract

“…These include HG-7-85-01 (Table 1), which uses a modified nilotinib-dasatinib hybrid structure to avoid gatekeeper mutations (57), and GNF-2, an allosteric ABL inhibitor that has been shown to be effective in combination with ATP-competitive ABL inhibitors (Table 1) (58,59).…”

Section: Preclinical Bcr-abl T315i Inhibitors: Recent Approachesmentioning

confidence: 99%

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

O’Hare

Deininger

Eide

et al. 2011

Clinical Cancer Research

130

104

View full text Add to dashboard Cite

Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL T315I . A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL T315I . The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL T315I mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL T315I in the development pipeline.

show abstract

Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants

Cited by 62 publications

References 42 publications

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

Contact Info

Product

Resources

About