Crenolanib: Difference between revisions

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 443232265

| IUPACName = 1-(2-<nowiki/>{5-[(3-methyloxetan-3-yl)methoxy]-1''H''-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine

| OtherNames = CP-868,596; AR-868,596-26

|Section1={{Chembox Identifiers

| IUPHAR_ligand = 7882

| CASNo_Ref = {{cascite|correct|??}}

| CASNo = 670220-88-9

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = LQF7I567TQ

| PubChem = 10366136

| ChEBI = 145365

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 2105728

| ChEMBL1_Ref = {{ebicite|changed|EBI}}

| ChEMBL1 = 2146086

| KEGG = D10102

| KEGG_Ref = {{keggcite|changed|kegg}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| SMILES = O(c5cc4ncn(c1nc3c(cc1)cccc3N2CCC(N)CC2)c4cc5)CC6(COC6)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|Section2={{Chembox Properties

| C=26 | H=29 | N=5 | O=2

| Appearance =

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| Solubility =

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

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'''Crenolanib''' besylate (CP-868,596-26 or AR-868,596-26, 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl) methoxy]-1H-benzimidazol-1-yl]- 8-quinolinyl]-, {{chem name|monobenzenesulfonate}}) is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including [[acute myeloid leukemia]] (AML),<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01657682?term=aml%2C+crenolanib&rank=1 |title=A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref><ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01522469?term=aml%2C+crenolanib&rank=2 |title=Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref> [[gastrointestinal stromal tumor]] (GIST),<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01243346?term=gist%2C+crenolanib&rank=1 |title=Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref> and [[glioma]].<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01393912?term=glioma%2C+crenolanib&rank=1 |title=PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref>

Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of [[wild-type]] and mutant isoforms of class III receptor tyrosine kinases (RTK) [[FLT3]] (FMS-like Tyrosine Kinase 3), [[PDGFR]] α (Platelet-Derived Growth Factor Receptor), and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to [[phosphorylated]] active kinases with the ‘DFG in’ conformation [[Structural motif|motif]].<ref>{{cite web |url=http://www.gistsupport.org/media/GISTS_2012/POSTER--AROG--AACR%202012_type%20I%20vs%20type%20II%20poster.pdf |title=CRENOLANIB, A NOVEL TYPE I, MUTANT -SPECIFIC INHIBITOR OF CLASS III RECEPTOR TYROSINE KINASES, PREFERENTIALLY BINDS TO PHOSPHORYLATED KINASES |author1=A. Ramachandran |author2=H. Marshall |author3=V. Jain |publisher=gistsupport.org |access-date=2014-04-08}}</ref>

== Background ==

Type III [[Receptor tyrosine kinase]], including [[FLT3]], [[PDGFRα]] and [[PDGFRβ]], have been directly implicated in the [[pathogenesis]] of [[epithelial]], [[mesenchymal]], and [[hematological malignancies]].<ref>{{cite journal |doi=10.1016/j.cell.2010.06.011 |title=Cell Signaling by Receptor Tyrosine Kinases |year=2010 |last1=Lemmon |first1=Mark A. |last2=Schlessinger |first2=Joseph |journal=Cell |volume=141 |issue=7 |pages=1117–34 |pmid=20602996 |pmc=2914105}}</ref>

Mutations of [[FLT3]] comprise one of the most frequently identified types of genetic alterations in acute myeloid leukemia.<ref name="ncbi.nlm.nih.gov">{{cite journal|title=Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications |date=2011-04-01 |pmc=3076284 |pmid=21453545 |doi=10.1186/1756-8722-4-13 |volume=4 |journal=J Hematol Oncol |pages=13 | last1 = Takahashi | first1 = S |doi-access=free }}</ref><ref>{{cite journal|title=Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia|journal=New England Journal of Medicine |volume=368 |issue=22 |year=2013 |pages=2059–2074 |issn=0028-4793 |doi=10.1056/NEJMoa1301689 |pmid=23634996 |pmc=3767041|author1=Cancer Genome Atlas Research Network |last2=Ley |first2=T. J. |last3=Miller |first3=C. |last4=Ding |first4=L. |last5=Raphael |first5=B. J. |last6=Mungall |first6=A. J. |last7=Robertson |first7=A. |last8=Hoadley |first8=K. |last9=Triche Jr |first9=T. J. |last10=Laird |first10=P. W. |last11=Baty |first11=J. D. |last12=Fulton |first12=L. L. |last13=Fulton |first13=R. |last14=Heath |first14=S. E. |last15=Kalicki-Veizer |first15=J. |last16=Kandoth |first16=C. |last17=Klco |first17=J. M. |last18=Koboldt |first18=D. C. |last19=Kanchi |first19=K. L. |last20=Kulkarni |first20=S. |last21=Lamprecht |first21=T. L. |last22=Larson |first22=D. E. |last23=Lin |first23=L. |last24=Lu |first24=C. |last25=McLellan |first25=M. D. |last26=McMichael |first26=J. F. |last27=Payton |first27=J. |last28=Schmidt |first28=H. |last29=Spencer |first29=D. H. |last30=Tomasson |first30=M. H. |display-authors=29 }}</ref> Approximately one-third of [[Acute myeloid leukemia|AML]] patients present with a mutation in this gene.<ref name="hindawi.com">{{cite journal|title=The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias |date=2013 |publisher=Hindawi.com |doi=10.1155/2013/275760 |doi-access=free |last1=Testa |first1=Ugo |last2=Pelosi |first2=Elvira |journal=Leukemia Research and Treatment |volume=2013 |pages=1–14 |pmid=23936658 |pmc=3725705 }}</ref> The majority of these mutations result in constitutive activation of downstream signaling pathways and aberrant cell growth.<ref name="ncbi.nlm.nih.gov"/> Mutations in FLT3 have also been reported in [[acute lymphoblastic leukemia]] (ALL)<ref>{{cite journal|title= Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children|date=2014-01-24 |pmid=10233379 |doi=10.1111/j.1365-2141.1999.01284.x |volume=105 |issue=1 |journal=Br. J. Haematol. |pages=155–62 | last1 = Xu | first1 = F | last2 = Taki | first2 = T | last3 = Yang | first3 = HW | last4 = Hanada | first4 = R | last5 = Hongo | first5 = T | last6 = Ohnishi | first6 = H | last7 = Kobayashi | first7 = M | last8 = Bessho | first8 = F | last9 = Yanagisawa | first9 = M | last10 = Hayashi | first10 = Y|s2cid=40898615 | doi-access = free }}</ref> and [[myelodysplastic syndrome]] (MDS).<ref>{{cite journal|title= Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines|date=2014-01-24 |pmid=9324277 |volume=11 |issue=10 |journal=Leukemia |pages=1605–9 | last1 = Yokota | first1 = S | last2 = Kiyoi | first2 = H | last3 = Nakao | first3 = M | last4 = Iwai | first4 = T | last5 = Misawa | first5 = S | last6 = Okuda | first6 = T | last7 = Sonoda | first7 = Y | last8 = Abe | first8 = T | last9 = Kahsima | first9 = K | last10 = Matsuo | first10 = Y | last11 = Naoe | first11 = T|doi=10.1038/sj.leu.2400812 |s2cid=12003642 | doi-access = }}</ref>

Activating mutations in [[PDGFRA]] have been detected in 5-12% of [[Gastrointestinal stromal tumor]].<ref>{{cite journal |doi=10.1126/science.1079666 |title=PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors |year=2003 |last1=Heinrich |first1=M. C. |journal=Science |volume=299 |issue=5607 |pages=708–10 |pmid=12522257 |last2=Corless |first2=CL |last3=Duensing |first3=A |last4=McGreevey |first4=L |last5=Chen |first5=CJ |last6=Joseph |first6=N |last7=Singer |first7=S |last8=Griffith |first8=DJ |last9=Haley |first9=A |last10=Town |first10=A |last11=Demetri |first11=GD |last12=Fletcher |first12=CD |last13=Fletcher |first13=JA|s2cid=11725958 }}</ref> Fusion of [[PDGFRA]] has been found to be responsible for hematological malignances like [[hypereosinophilic syndrome]].<ref name="Ref6">{{cite book |doi=10.1016/S0065-230X(06)97011-0 |pmid=17419949 |title=PDGF Receptors as Targets in Tumor Treatment |series=Advances in Cancer Research |year=2007 |last1=Östman |first1=Arne |last2=Heldin |first2=Carl‐Henrik |isbn=9780120066971 |volume=97 |pages=247–274}}</ref> The amplification of [[chromosome 4]]q12, the site of the [[PDGFRA]] gene{{Citation needed|date=September 2014}}, has been identified in 13-29% of adult [[gliomas]]{{Citation needed|date=September 2014}} and in 29% to 36% of diffuse intrinsic [[pons|pontine]] gliomas ([[DIPG]]){{Citation needed|date=September 2014}}, a subset of high-grade gliomas (HGG) in pediatric patients. Activation of [[PDGFRB]], a third member of the type III RTK family, has been implicated in the development of [[chronic myelomonocytic leukemia]] due to the fusion of [[PDGFRB]] with the TEL gene.<ref name="Ref6" /> Furthermore, [[PDGFB]] translocation to the COL1A1 gene locus has been identified to be responsible for [[dermatofibrosarcoma protuberans]] (DFSP).<ref name="Ref6" /> In cancer cells, [[PDGFR]] promotes tumor development and migration via proto-oncogenic downstream mediators like [[AKT]] and [[Mitogen-activated protein kinase kinase|MEK]]{{citation needed|date=September 2014}}. In [[stromal]] [[fibroblasts]], [[PDGFRα]] activation leads to local tissue invasion, production and secretion of [[VEGF]], and elevated intratumoral interstitial pressure{{citation needed|date=September 2014}}. In stromal [[pericytes]], [[PDGFRβ]] activation mediates vascular stability.<ref name="Ref6" /> Thus, either FLT3 or [[PDGF]]/[[PDGFR]] pathway is the primary driver of [[oncogenesis]] in the above malignancies and can be targeted by crenolanib therapy{{citation needed|date=September 2014}}.

== Mechanism ==

===[[FLT3]]: wild-type and mutant===

Crenolanib inhibits both wild type [[FLT3]] and its constitutively active mutations. In vitro studies have shown that crenolanib has low [[Dissociation constant|''K''_d]] for the [[FLT3]] enzyme with constitutively activating internal tandem duplication (ITD) mutations and [[tyrosine kinase]] domain (TKD) mutations, D835H and D835Y, as compared to wild type. Crenolanib tightly binds to [[FLT3]]-ITD, [[FLT3]]-D835H and [[FLT3]]-D835Y with [[Dissociation constant|''K''_d]] of 0.74 nM, 0.4 nM, and 0.18 nM, respectively.<ref name="Ref7">{{cite journal |doi=10.1158/1538-7445.AM2012-3683 |title=Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases |year=2012 |last1=Muralidhara |first1=C. |last2=Ramachandran |first2=A. |last3=Jain |first3=V. K. |journal=Cancer Research |volume=72 |issue=8 Supplement |page=3683}}</ref> Crenolanib inhibits the phosphorylation of the [[FLT3]]-ITD receptor in transfected TF-1 cells and the [[FLT3]]-D835Y TKD mutation in transfected Ba/F3 cells at nanomolar [[IC50]] concentrations of 1.3 nM and 8.8 nM, respectively.<ref name="Ref8">{{cite journal |doi=10.1158/1538-7445.am2012-3660 |title=Abstract 3660: Crenolanib: A next generation FLT3 inhibitor |year=2012 |last1=Galanis |first1=A. |last2=Rajkhowa |first2=T. |last3=Muralidhara |first3=C. |last4=Ramachandran |first4=A. |last5=Levis |first5=M. |journal=Cancer Research |volume=72 |issue=8 Supplement |page=3660}}</ref> [[Immunoblot]] experiments performed in the [[Molm14]] [[FLT3]]-ITD positive cell line show that crenolanib inhibits downstream signaling of [[FLT3]] at a concentration of 10 nM.<ref name="Ref8" /> [[MTT assay]] measurements of crenolanib [[cytotoxicity]] evaluated in the [[FLT3]]-ITD expressing cell lines [[Molm14]] and [[MV411]], showed that crenolanib is toxic at [[IC50]] concentrations of 7 nM and 8 nM, respectively.<ref name="Ref8" />

===PDGFRα: wild-type and mutant===

Crenolanib has been shown to inhibit [[PDGFRα]] with an [[IC50]] of 0.4&nbsp;ng/mL in porcine aortic epithelial cell lines. In [[Chinese hamster ovary|Chinese hamster ovary (CHO)]] cells expressing [[PDGFRα]], crenolanib inhibited the phosphorylation of wild type [[PDGFRα]] at an [[IC50]] of 10 nM.<ref name="Ref9">{{cite journal |doi=10.1158/1078-0432.CCR-12-0625 |title=Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors |year=2012 |last1=Heinrich |first1=M. C. |last2=Griffith |first2=D. |last3=McKinley |first3=A. |last4=Patterson |first4=J. |last5=Presnell |first5=A. |last6=Ramachandran |first6=A. |last7=Debiec-Rychter |first7=M. |journal=Clinical Cancer Research |volume=18 |issue=16 |pages=4375–84 |pmid=22745105|doi-access=free }}</ref> Additionally, crenolanib completely blocked [[PDGFRα]] phosphorylation and downstream [[AKT]] signaling at a concentration between 0.1 and 1 uM in Ink4a/Arf-/- mouse [[astrocytes]] transfected to stably co-express both human [[PDGFRα]] and [[PDGF]] AA.<ref>{{cite journal |doi=10.1158/1538-7445.am2011-1111 |title=Abstract 1111: Preclinical evaluation of CP868,596, a novel PDGFR Inhibitor for treatment of glioblastoma |year=2011 |last1=Yang |first1=X.-L. |last2=Mashimo |first2=T. |last3=Su |first3=Y. |last4=Vemireddy |first4=V. |last5=Guntipalli |first5=P. |last6=Ramachandran |first6=A. |last7=Chaudhary |first7=P. |last8=Mickey |first8=B. |last9=Hatanpaa |first9=K. |last10=Maher |first10=E. |last11=Bachoo |first11=R. M. |journal=Cancer Research |volume=71 |issue=8 Supplement |page=1111}}</ref> The [[lung cancer]] cell line H1703, which is reported to have amplification of both [[PDGFRA]] (4q12) and PDGFC (4q32) genes on chromosome 4, and also overexpress [[PDGFRα]], was sensitive to crenolanib with an [[IC50]] of ~80 nM.<ref>{{cite journal |doi=10.1158/1538-7445.am2011-3601 |title=Abstract 3601: CP-868,596, a highly potent and selective PDGFR TKI inhibits growth of PDGFR -driven lung cancer cells |year=2011 |last1=Peyton |first1=M. |last2=Chaudhary |first2=P. |last3=Ramachandran |first3=A. |last4=Minna |first4=J. |journal=Cancer Research |volume=71 |issue=8 Supplement |page=3601}}</ref> In [[Chinese hamster ovary cell|CHO]] cells expressing an activating exon 18 (D842V) [[PDGFRα]] mutation, crenolanib was effective at an [[IC50]] of 6nM and IC90 of 25nM. In addition, crenolanib also inhibited phosphorylation of the double mutants [[PDGFRα]] (V561D + D842V and T674I + D842V).<ref name="Ref9" />

===PDGFRβ: wild-type===

Crenolanib has been shown to inhibit [[PDGFRβ]] with an [[IC50]] of 0.8&nbsp;ng/mL in porcine aortic epithelial cell lines. Crenolanib inhibits the ability of recombinant [[PDGFRβ]] to phosphorylate a synthetic tyrosine substrate ([[poly-glutamic acid]]-tyrosine), with an [[IC50]] of 0.4&nbsp;ng/mL. Evaluation of the antitumor activity of crenolanib in a genetically engineered BSG DIPG mouse model showed that it is highly selective for [[PDGFRβ]] with an [[IC50]] of 10 nM when measured by BrdU assay and 1.25 uM by [[MTT assay]].

===C-Kit: wild-type and mutant===

Crenolanib has been shown to have [[IC50]] and Kd values of 67 nM and 78 nM, respectively, for wild type [[c-KIT]] in in vitro assays{{citation needed|reason=This claim doesn't have a citation. Reference 14 does NOT have actual Kd... it just says "still being determined"|date=September 2014}}. Similar assays show that crenolanib inhibits [[c-KIT]] activating mutations D816H and D816V with [[IC50]] concentrations of 5.4 and 2.5 nM, respectively.<ref name="Ref7" />{{citation needed|reason=This claim doesn't have a citation. Reference 14 does NOT have actual Kd... it just says "still being determined"|date=September 2014}} Human [[bone marrow]] [[progenitor cell]] growth assays showed that crenolanib has modest effects on [[GM-CSF]] and [[BFUE]] driven colony formation at the [[IC50]] concentration of 20 nM.<ref name="Ref8" />

Phase I single-agent<ref>{{cite journal |doi=10.1200/jco.2009.21.8487 |title=Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers |year=2009 |last1=Lewis |first1=N. L. |last2=Lewis |first2=L. D. |last3=Eder |first3=J. P. |last4=Reddy |first4=N. J. |last5=Guo |first5=F. |last6=Pierce |first6=K. J. |last7=Olszanski |first7=A. J. |last8=Cohen |first8=R. B. |journal=Journal of Clinical Oncology |volume=27 |issue=31 |pages=5262–9 |pmid=19738123 |pmc=2773478}}</ref> and Phase Ib combination<ref>{{cite journal |doi=10.1038/sj.bjc.6605941 |title=Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor |year=2010 |last1=Michael |first1=M |last2=Vlahovic |first2=G |last3=Khamly |first3=K |last4=Pierce |first4=K J |last5=Guo |first5=F |last6=Olszanski |first6=A J |journal=British Journal of Cancer |volume=103 |issue=10 |pages=1554–61 |pmid=20959830 |pmc=2990584}}</ref> studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of Crenolanib administered alone or in combination with [[docetaxel]] with or without [[axitinib]] have been completed. Results suggest that Crenolanib is well tolerated as a single agent, and can also be safely combined with [[docetaxel]] and [[axitinib]] due to their non-overlapping toxicity profiles.

== Clinical trials ==

*{{ClinicalTrialsGov|NCT01229644|A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas}}

*{{ClinicalTrialsGov|NCT01243346|Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene}}

*{{ClinicalTrialsGov|NCT01393912|PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma}}

*{{ClinicalTrialsGov|NCT01522469|Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations}}

*{{ClinicalTrialsGov|NCT01657682|A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations}}

{{Growth factor receptor modulators}}