Flt3 (Kd = 1.6±0.7 nM)
Quizartinib HCl (AC-220; AC-010220) is a potent and selective inhibitor of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase (Biochemical binding Kd for FLT3: 1.6 ± 0.7 nM). It also shows affinity for closely related receptor tyrosine kinases including KIT, PDGFRα, PDGFRβ, RET, and CSF1R, with binding constants (Kd) within 10-fold of that for FLT3. Additionally, it binds to FLT1, FLT4, DDR1, and VEGFR2 with Kd within 100-fold of FLT3, as determined by a KinomeScan panel of 402 kinase assays. [1]

In vitro activity: AC220, a unique, potent and selective inhibitor of FLT3, has high affinity for FLT3 with a Kd value of 1.6 nM. AC220 inhibits the autophosphorylation of FLT3 in the human leukemia cell lines MV4-11 which harbor a homozygous FLT3-ITD mutation and is FLT3 dependent, and RS4;11 which expresses wild-type FLT3 with IC50 values of 1.1 nM and 4.2 nM, respectively. AC220 is the most potent cellular FLT3-ITD inhibitor, leading to the most significant inhibition of MV4-11 cell proliferation with IC50 of 0.56 nM compared to all other FLT3 inhibitors whose IC50 values range from 0.87 nM to 64 nM. AC220 has no inhibitory activity against the proliferation of A375 cells which harbor an activating mutation in BRAF and are not FLT3 dependent, indicating a large window between FLT3 inhibition and general cytotoxic effects.

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Kinase Assay: To measure inhibition of FLT3 autophosphorylation, MV4-11 or RS4;11 cells are cultured in low serum media (0.5% FBS) overnight and seeded at a density of 400 000 cells per well in a 96-well plate the following day. The cells are incubated with different concentrations of AC220 for 2 hours at 37 °C. To induce FLT3 autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand is added for 15 minutes after the 2-hour AC220 incubation. Cell lysates are prepared and incubated in 96-well plates precoated with a total FLT3 capture antibody. The coated plates are incubated with either a biotinylated antibody against FLT3 to detect total FLT3 or an antibody against phosphotyrosines to detect FLT3 autophosphorylation. In both cases, a SULFO-tagged streptavidin secondary antibody is used for electrochemiluminescence detection on the Meso Scale Discovery platform. The concentration of AC220 that inhibits FLT3-ITD or TLT3-WT autophosphorylation by 50% represents IC50 value.

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Cell Assay: Cells (MV4-11 and RS4;11 cells) are cultured overnight in low serum media (0.5% FBS), seeded in a 96-well plate at 40 000 cells per well and exposed to AC220 for 72 hours at 37 °C. Cell viability is measured using the Cell Titer-Blue Cell Viability Assay.

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In biochemical binding assays, Quizartinib bound to FLT3 with a Kd of 1.6 ± 0.7 nM. [1]
In cellular assays using the FLT3-ITD mutant human leukemia cell line MV4-11, Quizartinib inhibited FLT3 autophosphorylation with an IC50 of 1.1 ± 0.1 nM and cell proliferation with an IC50 of 0.56 ± 0.3 nM. [1]
In the wild-type FLT3-expressing cell line RS4;11 (stimulated with FLT3 ligand), Quizartinib inhibited FLT3 autophosphorylation with an IC50 of 4.2 ± 0.3 nM. [1]
Quizartinib showed no significant inhibitory effect on the proliferation of A375 cells (BRAF-mutant, FLT3-independent) at concentrations up to 10,000 nM, indicating selectivity and lack of general cytotoxicity. [1]
In primary AML blast cells isolated from patients with FLT3-ITD mutations, Quizartinib inhibited FLT3 phosphorylation with an IC50 of approximately 2 nM and reduced cell viability with IC50s ranging from 0.3 nM to 2 nM across samples from five different patients. [1]

Oral administration of AC220 (10 mg/kg) induces time-dependent inhibition of FLT3 autophosphorylation in the FLT3-ITD–dependent MV4-11 tumor xenograft mouse model; the inhibition being 90% at 2 hours and 40% at 24 hours. AC220 significantly extends survival in a mouse model of FLT3-ITD AML with doses as low as 1 mg/kg given orally once a day. Treatment with AC220 at 10 mg/kg for 28 days results in rapid and complete regression of tumors in all mice with no tumor regrowth during the 60-day posttreatment period. AC220 displays more significant efficacy compared to sunitinib treatment which causes tumors to shrink slowly and resume growth immediately upon discontinuation of treatment in all but one of the mice.

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In a subcutaneous MV4-11 (FLT3-ITD) xenograft mouse model, a single oral dose of Quizartinib (10 mg/kg) inhibited FLT3 autophosphorylation in tumors by 90% at 2 hours and by 40% at 24 hours post-dose. [1]
In the same subcutaneous MV4-11 xenograft model, oral administration of Quizartinib (10 mg/kg once daily for 28 days) resulted in rapid and complete tumor regression in all treated mice, with no tumor regrowth observed during a 60-day post-treatment observation period. [1]
In a mouse bone marrow engraftment model of FLT3-ITD AML (MV4-11 cells), once-daily oral treatment with Quizartinib for 30 days prolonged survival in a dose-dependent manner. At 10 mg/kg, 80% of animals survived until the study endpoint (day 172, 119 days post-treatment cessation), representing a >250% increase in lifespan. At 1 mg/kg, a significant increase in mean survival time (55% increase) was observed. [1]

Biochemical kinase binding assays[1]
KinomeScan kinase binding assays were performed as previously described. For the FLT3 assay, we used a kinase construct that spanned the catalytic domain only (amino acids 592 to 969 in NP_004110.2). This construct does not include the juxtamembrane domain and is designed to measure the intrinsic binding affinity of the open FLT3 active site for inhibitors.

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Biochemical kinase binding affinity (Kd) was determined using a KinomeScan assay. A recombinant protein containing the FLT3 catalytic domain (amino acids 592-969) was used. Compounds were screened against a panel of 402 human kinase assays. For the primary screen, compounds were tested at a single concentration of 10 µM. For kinases identified as hits in the primary screen, dissociation constants (Kd) were determined. For Quizartinib, Kd was also measured for every kinase not identified as a hit in the primary screen to ensure no targets were missed. The assay measures the ability of the test compound to displace an immobilized, active-site directed ligand. [1]

Cellular assays[1]
MV4-11 and RS4;11 cells were cultured in Iscove media with 10% fetal bovine serum (FBS) and RPMI complete with 10% FBS, respectively. For proliferation assays, cells were cultured overnight in low serum media (0.5% FBS), then seeded in a 96-well plate at 40 000 cells per well. Inhibitors were added to the cells and incubated at 37°C for 72 hours. Cell viability was measured using the Cell Titer-Blue Cell Viability Assay from Promega. To measure inhibition of FLT3 autophosphorylation, cells were cultured in low serum media (0.5% FBS) overnight and seeded at a density of 400 000 cells per well in a 96-well plate the following day. The cells were incubated with inhibitors for 2 hours at 37°C. To induce FLT3 autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand was added for 15 minutes after the 2-hour compound incubation. Cell lysates were prepared and incubated in 96-well plates precoated with a total FLT3 capture antibody. The coated plates were incubated with either a biotinylated antibody against FLT3 to detect total FLT3 or an antibody against phosphotyrosines to detect FLT3 autophosphorylation. In both cases, a SULFO-tagged streptavidin secondary antibody was used for electrochemiluminescence detection on the Meso Scale Discovery platform.

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Primary cell assays1]
Leukemia cell specimens were provided by the Sidney Kimmel Cancer Center at the Johns Hopkins Tumor and Cell Procurement Bank, supported by the Regional Oncology Research Center Grant no. 2 P30 CA 006973-44. Mononuclear cells were isolated from whole blood or marrow using density gradient centrifugation with Ficoll-Hypaque and stored in liquid nitrogen in FBS with 10% dimethyl sulfoxide. When used, frozen samples were thawed rapidly, incubated in culture medium overnight, then subjected to another round of density centrifugation (with added DNAse) to eliminate cells that had undergone apoptosis from the freeze-thaw cycle. The FLT3 mutation status was determined as described.46 Cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay.19 To assess FLT3 phosphorylation by Western blot, patient-derived leukemia blasts were washed in phosphate-buffered saline, then lysed by resuspending them in lysis buffer (20 mM Tris, pH 7.4, 100 mM NaCl, 1% Igepal, 1 mM EDTA, 2 mM NaVO4, plus Complete Protease Inhibitor Cocktail) for 30 minutes while rocking. The lysate was clarified by centrifugation at 18 000 g and the supernatant was assayed for protein (Bio-Rad). Anti-FLT3 (S18) antibody was added to the extract for overnight incubation; then protein A sepharose was added for 2 additional hours. After sodium dodecylsulfate polyacrylamide electrophoresis and transfer to Immobilon membranes, immunoblotting was performed with antiphosphotyrosine antibody (4G10) to detect phosphorylated FLT3, then stripped and reprobed with anti-FLT3 antibody to measure total FLT3. Proteins were visualized using enhanced chemiluminescence. To quantitate phospho-FLT3 levels, cell lysates were assayed for phospho-FLT3 and total FLT3 by ELISA as described for “Cellular assays.”

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For cellular FLT3 autophosphorylation inhibition assays, MV4-11 or RS4;11 cells were cultured overnight in low serum media (0.5% FBS). Cells were then seeded in 96-well plates (400,000 cells/well) and incubated with inhibitors for 2 hours at 37°C. For RS4;11 cells, FLT3 ligand (100 ng/mL) was added for the final 15 minutes to induce phosphorylation. Cells were lysed, and lysates were transferred to 96-well plates pre-coated with an anti-FLT3 capture antibody. Phosphorylated FLT3 was detected using an anti-phosphotyrosine antibody, and total FLT3 was detected using a biotinylated anti-FLT3 antibody, followed by a SULFO-tagged streptavidin secondary antibody and electrochemiluminescence detection. [1]
For cell proliferation assays, MV4-11 cells were cultured overnight in low serum media (0.5% FBS), then seeded in 96-well plates (40,000 cells/well). Inhibitors were added, and cells were incubated for 72 hours at 37°C. Cell viability was measured using a resazurin-based (Cell Titer-Blue) assay. [1]
For primary AML blast cell assays, mononuclear cells were isolated from patient blood or marrow samples using density gradient centrifugation. For viability assays, cells were treated with Quizartinib for 72 hours, and cell viability was assessed using the MTT assay. For phosphorylation analysis, cells were treated with Quizartinib for 1 hour, then lysed. Phospho-FLT3 and total FLT3 levels were quantified either by Western blot (following immunoprecipitation with anti-FLT3 antibody) or by a more sensitive electrochemiluminescence-based ELISA method similar to the cellular assay described above. [1]

Formulated in 22% hydroxypropyl-β-cyclodextrin; 10 mg/kg; Oral gavage Female NU/NU or severe combined immunodeficient mice implanted with MV4-11 cells
\nMice: The mice used are female nu/NU or severe combined immunodeficient mice. Quizartinib (hydrochloride salt) is formulated in 22% hydroxypropyl-β-cyclodextrin, CEP-701 is formulated in 20% gelucire 44/14 in water (vol/vol), MLN-518 and SU 11248 are formulated in 10 mM sodium citrate (pH 3.5), PKC-412 is formulated in 3:1 gelucire 44/14-propylene glycol (vol/vol), and Bay 43-9006 is formulated in 80% PEG-400. Compound concentrations are selected in a volume of 10 mL/kg to deliver the intended dose. Oral gavage is used to administer compounds, and plasma samples are taken 0,25,0.5,1,2,4,6, and 24 hours after dosing. In order to obtain three independent plasma concentration time courses, eye bleeds (150 μL) are obtained semilongitudinally using three groups of three animals each, taking two to three time points per animal. Using four volumes of acetonitrile containing an internal standard, plasma samples and controls (25 μL) are extracted, and liquid chromatography tandem mass spectrometry is used for analysis.

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\n
\nPharmacokinetic studies[1]
\nFemale NU/NU or severe combined immunodeficient mice were purchased from Charles River Laboratories or Harlan. AC220 (hydrochloride salt) was formulated in 22% hydroxypropyl-β-cyclodextrin, CEP-701 was formulated in 20% gelucire 44/14 in water (vol/vol), MLN-518 and sunitinib were formulated in 10 mM sodium citrate (pH 3.5), PKC-412 was formulated in 3:1 gelucire 44/14–propylene glycol (vol/vol), and sorafenib (toluene sulfonate salt) was formulated in 80% PEG-400. Compound concentrations were chosen to deliver the desired dose in a volume of 10 mL/kg. Compounds were administered by oral gavage and plasma samples collected 0.25, 0.5, 1, 2, 4, 6, and 24 hours after dosing. To collect plasma samples, eye bleeds (150 μL) were taken semilongitudinally using 3 groups of 3 animals each, taking 2 to 3 time points per animal to obtain a total of 3 independent plasma concentration time courses. Plasma samples and controls (25 μL) were extracted with 4 volumes of acetonitrile containing an internal standard and analyzed by liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were obtained by fitting the normalized liquid chromatography tandem mass spectrometry peak areas to a noncompartmental model using the linear trapezoidal estimation method in the WinNonlin software package. Mouse studies at Ambit complied with the recommendations of the “Guide for Care and Use of Laboratory Animals”45 with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care.

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\n
\nAnimal efficacy studies[1]
\nSubcutaneous xenograft model.[1]
\nThis model was performed at Ambit to measure in vivo inhibition of FLT3, and by Piedmont Research Center LLC to determine antitumor efficacy, following published procedures. Compounds were formulated and administered as described for pharmacokinetic studies. To measure FLT3 inhibition, tumors were harvested at 2 or 24 hours after compound administration, weighed, and lysed by mechanical dissociation. Tumor lysates were cleared of protein and tissue fragments by centrifugation at 835g for 15 minutes. Cleared lysates were assayed for total and phosphorylated FLT3 using the electrochemiluminescence-based enzyme-linked immunoassay (ELISA) described in “Cellular assays.”

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\n
\nBone marrow engraftment model.[1]
\nThe model was performed according to published procedures.20 For intravenous bone marrow engraftment, nonobese diabetic/severe combined immunodeficient mice were acclimated for 2 weeks before pretreatment with 150 mg/kg cyclophosphamide delivered intraperitoneally once a day for 2 days. After a 48-hour rest period, animals were given an intravenous injection of 5 × 106 MV4-11 cells into the tail vein. AC220 was formulated and delivered as described for pharmacokinetic studies.

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\n

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\nFor pharmacokinetic studies, Quizartinib (hydrochloride salt) was formulated in 22% hydroxypropyl-β-cyclodextrin solution. Mice were administered a single oral dose via gavage at volumes of 10 mL/kg. Blood samples were collected at specified time points post-dose for plasma concentration analysis. [1]
\nFor the subcutaneous MV4-11 xenograft efficacy study, mice bearing tumors (~200-250 mm³) were treated orally with Quizartinib (10 mg/kg) once daily for 28 days. Tumor size was monitored during treatment and for an additional 60 days after treatment cessation. [1]
\nFor the bone marrow engraftment efficacy model, NOD/SCID mice were pretreated with cyclophosphamide (150 mg/kg i.p. daily for 2 days). After a 48-hour rest, 5×10⁶ MV4-11 cells were injected intravenously. After 23 days, treatment with Quizartinib (0.1, 1, or 10 mg/kg) or vehicle was initiated orally once daily for 30 days. Survival was monitored. [1]
\nFor the FLT3 inhibition pharmacodynamic study in the subcutaneous xenograft model, mice bearing MV4-11 tumors received a single oral dose of Quizartinib (10 mg/kg). Tumors were harvested at 2 and 24 hours post-dose for analysis of phospho-FLT3 and total FLT3 levels by ELISA. [1]

Absorption, Distribution and Excretion
In healthy subjects, the mean (standard deviation) absolute bioavailability of quezartinib in tablet form was 71% (±7%). Following oral administration on an empty stomach, the median time to peak concentration (Tmax) for quezartinib and AC886 in healthy subjects was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively. In newly diagnosed acute myeloid leukemia patients, after once-daily administration of 35.4 mg quezartinib, the Cmax and AUC0-24h during induction therapy were 140 ng/mL (71%) and 2,680 ng·h/mL (85%), respectively, while those during consolidation therapy were 204 ng/mL (64%) and 3,930 ng·h/mL (78%), respectively. During induction therapy, the Cmax and AUC0-24h of metabolite AC886 were estimated to be 163 ng/mL (52%) and 3,590 ng·h/mL (51%), respectively; during consolidation therapy, they were estimated to be 172 ng/mL (47%) and 3,800 ng·h/mL (46%), respectively. Increasing the once-daily dose of quizartinib to 53 mg increased the Cmax and AUC0-24h of quizartinib to 529 ng/mL (60%) and 10,200 ng·h/mL (75%) at steady state. The Cmax and AUC0-24h of metabolite AC886 also increased to 262 ng/mL (48%) and 5,790 ng·h/mL (46%), respectively. No clinically significant differences in quizartinib pharmacokinetics were observed when co-administered with a high-fat, high-calorie meal.
Following a single 53 mg dose of radiolabeled quizartinib in healthy subjects, 76.3% of the total radioactive material was recovered from feces (4% of which was unchanged) and 1.64% from urine.
The estimated steady-state volume of distribution in healthy subjects was 275 L (17%).
The estimated total clearance of quizartinib in healthy subjects was 2.23 L/h (29%).
Metabolism/Metabolites
In vitro studies showed that quizartinib is primarily metabolized via CYP3A4/5 oxidation, while the formation and metabolism of AC886 are also accomplished by CYP3A4/5.
Biological Half-Life
The mean (standard deviation) effective half-life in newly diagnosed acute myeloid leukemia (AML) patients receiving maintenance therapy was 81 hours (±73) and 136 hours (±113), respectively.

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In mice, after a single oral dose of 10 mg/kg of Quizartinib, the peak plasma concentration (Cmax) reached 3.8 ± 0.4 µM (approximately 2100 ng/mL), and the time to peak concentration (Tmax) was 1.5 ± 0.9 h. The area under the plasma concentration-time curve (AUC0-24h) from 0 to 24 hours was 35 ± 4 µM×h. The apparent plasma half-life was approximately 4 hours. [1]
In mice, plasma exposure (Cmax and AUC0-24h) increased proportionally with the oral dose, ranging from 0.1 to approximately 30 mg/kg. [1] In rats, the oral bioavailability of Quizartinib was approximately 40% (comparing oral and intravenous administration at a dose of 3 mg/kg). [1]
The plasma protein binding of Quizartinib in mouse plasma was approximately 99%. [1]

Hepatotoxicity
In premarketing clinical trials of quizartinib in patients with acute myeloid leukemia (AML), elevated alanine aminotransferase (ALT) levels occurred in 10% to 16% of patients, with 1% to 3% experiencing ALT elevations exceeding five times the upper limit of normal (ULN). However, similar ALT elevations have been reported in chemotherapy-naïve quizartinib-naïve patients, and in most cases, these elevations are transient, asymptomatic, and unrelated to serum bilirubin elevation. Intermittent liver enzyme elevations are not uncommon in treatment-naïve AML patients due to bacterial, viral, and opportunistic infections. While occasional cases of acute liver injury and liver failure have been observed in quizartinib registration trials, all cases were attributed to other comorbidities and factors (multi-organ failure) unrelated to quizartinib. No clinically significant liver injury cases related to quizartinib treatment have been reported since its approval in the United States. Probability Score: E (Unlikely to be the cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of use during lactation
There is currently no information on the clinical use of quizartinib during lactation. Because quizartinib binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk may be very low. However, the manufacturer recommends discontinuing breastfeeding during quizartinib treatment and for one month after the last dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding>
The in vitro plasma protein binding rates of quizartinib and AC886 are both 99% or higher. In in vitro experiments, the blood concentration/plasma concentration ratios of quizartinib and AC886 were 0.79–1.30 and 1.36–3.19, respectively. In 28-day subcutaneous xenograft studies and 30-day bone marrow transplant studies in mice, treatment with doses up to 10 mg/kg/day of quizartinib did not cause significant weight loss or other significant toxic reactions. [1]

[1]. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood, 2009, 114(14), 2984-2992.

[2]. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014 Feb 10;25(2):226-42.

[3]. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64.

Pharmacodynamics
In a mouse model of FLT3-ITD-dependent leukemia, quinzartinib demonstrated antitumor activity. In vitro studies have shown that quinzartinib is a major inhibitor of slow-delayed rectified potassium currents (IKs). In patients with acute myeloid leukemia (AML) treated with quinzartinib, the daily dose was 90 mg for women and 135 mg for men for 28 days. Following treatment, the median levels of phosphorylated FLT3 (pFLT3) and total FLT3 (tFLT3) decreased from 3312 RLU and 5639 RLU on day 1 to 1235 RLU and 142 RLU on day 8, respectively. Furthermore, pFLT3 levels were significantly higher in ITD-positive patients than in non-ITD-positive patients on day 1 (p < 0.0001, Mann-Whitney test). However, pFLT3 levels decreased to similar levels regardless of whether the patient carried an ITD mutation. Exposure-response analysis predicted that, during maintenance therapy, at dose levels of 26.5 mg and 53 mg, the median QTcF interval would be prolonged by concentration-dependently by 18 and 24 ms to reach the steady-state median Cmax [upper limit of two-sided 90% confidence interval (CI): 21 and 27 ms]. Quizartinib is a second-generation FLT3 inhibitor specifically optimized for high efficacy and selectivity against FLT3 for the treatment of acute myeloid leukemia (AML). [1] It is a diarylurea compound. [1] Quantitative analysis using KinomeScan showed that the selectivity profile of Quizartinib exhibited high selectivity for a small number of kinases, primarily belonging to the class III receptor tyrosine kinase family, with a selectivity score comparable to other known selective kinase inhibitors such as imatinib and gefitinib. [1]
Its pharmacokinetic characteristics, including good oral absorption, dose-proportional exposure, and a half-life supporting once-daily dosing, combined with its high efficacy and selectivity, made it unique among FLT3 inhibitors at the time and met the ideal characteristics for clinical FLT3 inhibitors. [1]

C29H34CL2N6O4S

633.59

632.174

C, 54.98; H, 5.41; Cl, 11.19; N, 13.26; O, 10.10; S, 5.06

1132827-21-4

1132827-21-4 (HCl);950769-58-1;

24889392

Typically exists as White to off-white solid at room temperature

6.893

2

8

8

40

849

0

CC(C)(C)C1=CC(=NC(=O)NC2=CC=C(C=C2)C3=CN4C5=C(C=C(C=C5)OCCN6CCOCC6)SC4=N3)NO1.Cl.Cl

CVWXJKQAOSCOAB-UHFFFAOYSA-N

InChI=1S/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36)

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 HCl or AC010220 HCl; AC220 diHCl; AC 220; AC-220 dihydrochloride; AC010220; Quizartinib dihydrochloride; 1132827-21-4; AC-220 dihydrochloride; vanflyta; quizartinib hydrochloride; AC 010220 (dihydrochloride); AC010220.2HCL; WK7Q6ZIZ10; AC-010220; AC 010220; AC010220

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)