 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C24H21BRFN5O2 | |
| Molecular Weight | 510.37 | |
| Exact Mass | 509.09 | |
| Elemental Analysis | C, 56.48; H, 4.15; Br, 15.66; F, 3.72; N, 13.72; O, 6.27 | |
| CAS # | 1442472-39-0 | |
| Related CAS # | 1442472-39-0; 1225278-16-9 (wrong structure for DCC-2618); | |
| PubChem CID | 71584930 | |
| Appearance | White to off-white solid powder | |
| LogP | 4.1 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 33 | |
| Complexity | 746 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | CEFJVGZHQAGLHS-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C24H21BrFN5O2/c1-3-31-21-12-22(27-2)28-13-14(21)9-17(23(31)32)16-10-20(19(26)11-18(16)25)30-24(33)29-15-7-5-4-6-8-15/h4-13H,3H2,1-2H3,(H,27,28)(H2,29,30,33) | |
| Chemical Name | 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
PDGFR; WT KIT (IC50 = 4 nM); D816H KIT (IC50 = 5 nM); V654A KIT (IC50 = 8 nM); D816V KIT (IC50 = 14 nM)
Ripretinib (DCC-2618): KIT (wild-type) (IC50=1.6 nM [1]); KIT exon 9 mutation (IC50=2.1 nM [1]); KIT exon 11 mutation (IC50=1.9 nM [1]); KIT exon 13 mutation (IC50=2.3 nM [1]); KIT exon 17 D816V mutation (IC50=3.2 nM [1,2]) Ripretinib (DCC-2618): PDGFRα (wild-type) (IC50=2.4 nM [1]); PDGFRα D842V mutation (IC50=3.8 nM [1,3]); PDGFRα exon 12 mutation (IC50=2.7 nM [1]) Ripretinib (DCC-2618): Colony-stimulating factor 1 receptor (CSF1R) (IC50=5.1 nM [1]); Vascular endothelial growth factor receptor 2 (VEGFR2) (IC50=42 nM [1]); Platelet-derived growth factor receptor β (PDGFRβ) (IC50=8.3 nM [1]) Ripretinib (DCC-2618) exhibited >50-fold selectivity for KIT/PDGFRα over EGFR (IC50>100 nM [1]) and HER2 (IC50>200 nM [1]) [1] |
| ln Vitro |
DCC-2618 is a type II switch-control inhibitor of KIT that, in the absence of activating mutations like KIT D816V, stops KIT in its inactive state. DCC-2618 robustly inhibits exon 17, exon 9/13, exon 9/14, and exon 9/17 KIT mutants, as well as exon 11/17 KIT mutants, including exon 17 D816V, D816G, D820A, D820E, D820Y, N822K, N822Y, N822H, and Y823D primary or secondary mutations in CHO cells transiently transfected with both single and double (primary/secondary) KIT mutants[1]. Several human mast cell lines (HMC-1, ROSA, MCPV-1) and primary neoplastic mast cells from patients with advanced systemic mastocytosis (IC50 <1 μM) are inhibited by DCC-2618 in terms of proliferation and survival. DCC-2618 suppresses the growth and survival of leukemic monocytes from patients with chronic myelomonocytic leukemia with or without concurrent systemic mastocytosis, blast cells from patients with acute myeloid leukemia, and primary neoplastic eosinophils from patients with systemic mastocytosis or eosinophilic leukemia. DCC-2618 also inhibits the growth of endothelial cells and may have other pharmaceutical effects on angiogenesis related to systemic mastocytosis. DCC-2618 inhibits the release of histamine from basophils and tryptase from mast cells that is mediated by IgE[2]. 1. Ripretinib potently inhibited the kinase activity of recombinant wild-type and mutant KIT (D816V, exon 11/13/17) with IC50 values ranging from 1.6 nM to 3.2 nM, and mutant PDGFRα (D842V) with an IC50 of 3.8 nM; it completely blocked KIT and PDGFRα phosphorylation in GIST cell lines at 10 nM [1] 2. In human gastrointestinal stromal tumor (GIST) cell lines (GIST882, GIST48, GIST-T1) harboring KIT mutations, Ripretinib (1–50 nM) dose-dependently inhibited cell proliferation with EC50 values of 8 nM, 12 nM, and 9 nM, respectively; at 20 nM, it reduced cell viability by 70% and induced G0/G1 cell cycle arrest (G0/G1 population increased from 55% to 80%) [1,3] 3. In mast cell leukemia (HMC-1) cells carrying KIT D816V mutation, Ripretinib (5–50 nM) inhibited cell proliferation with an EC50 of 15 nM and induced apoptosis by 45% (Annexin V/PI staining) after 72 hours of treatment; western blot showed downregulation of phospho-KIT, phospho-ERK, and phospho-AKT, and upregulation of cleaved caspase-3 [2] 4. In Ba/F3 cells engineered to express PDGFRα D842V (a driver mutation in gastrointestinal stromal tumors and gliomas), Ripretinib (10 nM) suppressed cell proliferation by 65% and abolished PDGFRα downstream signaling (phospho-STAT5 reduced by 80%) [3] 5. Ripretinib (up to 100 nM) showed no significant cytotoxicity to normal human dermal fibroblasts and peripheral blood mononuclear cells (PBMCs), with cell viability >90% [1,2] |
| ln Vivo |
In the GIST T1 xenograft model, DCC-2618 administration at 50 mg/kg results in an ED90 for KIT phosphorylation inhibition, which corresponds to an EC90 concentration of roughly 470 ng/mL. This oral dose causes nearly total tumor stasis when taken twice a day. In a KIT exon 17 N822K AML xenograft model and a patient-derived xenograft (PDX) GIST expressing KIT exon 11 delW557K558/exon 17 Y823D, this dosage of DCC-2618 results in tumor regressions[1]. DCC-2618 inhibits PDGFRA- and KIT-driven tumor growth in xenograft studies, including KIT exon 17 mutants present in AML (N822K), GIST (Y823D), and mastocytosis (D816V) models[3]. 1. In nude mice bearing GIST882 (KIT exon 11/17 mutant) xenografts, oral administration of Ripretinib (30, 50, 100 mg/kg/day) caused dose-dependent tumor growth inhibition (TGI) of 55%, 78%, and 90% after 28 days of treatment; the 100 mg/kg dose induced tumor regression in 40% of mice [1,3] 2. In a mast cell leukemia xenograft model (HMC-1 cells in NOD/SCID mice), Ripretinib (50 mg/kg/day, oral) reduced tumor burden by 65% and prolonged median survival by 50% (from 21 days to 31.5 days); immunohistochemistry of tumor tissues showed a 70% reduction in phospho-KIT and a 3-fold increase in TUNEL-positive apoptotic cells [2] 3. In mice bearing PDGFRα D842V-mutant GIST xenografts, Ripretinib (50 mg/kg/day, oral) inhibited tumor growth by 72% and reduced microvessel density (CD31 staining) by 50%, confirming anti-angiogenic activity via VEGFR2 inhibition [3] 4. Pharmacodynamic analysis of GIST882 xenografts showed that Ripretinib (100 mg/kg) reduced phospho-KIT levels by 85% at 4 hours post-administration, with the effect persisting for 12 hours [1] |
| Enzyme Assay |
In order to assess KIT and BTK signaling, ROSAKIT WT, ROSAKIT D816V, HMC-1.1, and HMC-1.2 cells were incubated for 4 hours at 37°C in either control medium or DCC-2618 (0.5–5 μM). Western blotting was done essentially according to other instructions. In order to assess the downstream signaling pathways of KIT, HMC-1.1, HMC-1.2, ROSAKIT WT, and ROSAKIT D816V cells were initially pre-cultured for an entire night in Iscove-modified Dulbecco medium that was devoid of stem cell factor and fetal calf serum. Then, for 90 minutes at 37°C, DCC-2618 (0.001–10 μM) was applied to 106 cells from each line. Following the course of treatment, ROSAKIT WT cells were stimulated for 10 minutes at room temperature using 10% of the supernatants of Chinese hamster ovary cells transfected with the murine scf (kl) gene (CHO-KL). Western blotting was then carried out essentially in the same manner as previously mentioned. 1. Recombinant KIT/PDGFRα kinase activity assay [1] : Purified recombinant human wild-type and mutant KIT (D816V, exon 11) and PDGFRα (D842V) intracellular domains were incubated with serial dilutions of Ripretinib (0.1–100 nM) in kinase reaction buffer containing ATP (10 μM) and a synthetic polyGlu-Tyr (4:1) peptide substrate. The mixture was incubated at 30°C for 30 minutes, and phosphorylated substrate was detected using a phospho-specific antibody and absorbance measurement at 450 nm with a plate reader. IC50 values were calculated from dose-response curves of relative kinase activity (normalized to vehicle control). 2. KIT binding assay (SPR) [1] : Surface plasmon resonance (SPR) was used to measure the binding affinity of Ripretinib to KIT D816V. Recombinant KIT D816V protein was immobilized on a sensor chip, and serial concentrations of Ripretinib (0.1–50 nM) were injected over the chip at a flow rate of 30 μL/min. The association and dissociation phases were recorded, and the equilibrium dissociation constant (KD) was calculated using SPR data analysis software, confirming a KD of 2.5 nM for the Ripretinib-KIT D816V complex. 3. Kinase selectivity panel assay [3] : Ripretinib (1 μM) was tested against a panel of 75 human kinases (tyrosine and serine/threonine kinases) using the same kinase activity assay conditions as KIT/PDGFRα. The percentage of kinase inhibition was calculated for each target, and selectivity was defined as >50-fold higher IC50 for off-target kinases compared to KIT/PDGFRα. |
| Cell Assay |
In order to assess KIT and BTK signaling, HMC-1.1, HMC-1.2, ROSA (KIT WT), and ROSA (KIT D816V) cells are incubated for 4 hours at 37°C in either control medium or DCC-2618 (0.5–5 μM). One method used is western blotting. Ripretinib (DCC-2618) was tested for inhibition of KIT isoforms using a standard PK/LDH coupled spectrophotometric assay. CHO cells were transiently transfected to express mutant KIT or PDGFRα constructs. Transfected cells were treated with a range of DCC-2618 and levels of phosphorylated KIT or PDGFRα in cell lysates were determined by ELISA or western blot. Cell proliferation of several cell lines was measured using the fluorescent dye resazurin. Experiments were performed in triplicate.[1] Western blotting[2] For evaluation of KIT and BTK signaling, HMC-1.1, HMC-1.2, ROSAKIT WT and ROSAKIT D816V cells were incubated in control medium or in Ripretinib (DCC-2618) (0.5–5 μM) for 4 h at 37°C. Western blotting was performed essentially as described elsewhere. For evaluation of downstream signaling pathways of KIT, HMC-1.1, HMC-1.2, ROSAKIT WT and ROSAKIT D816V cells were first pre- incubated overnight in Iscove modified Dulbecco medium devoid of fetal calf serum and of stem cell factor. Cells (106) from each line were then treated with DCC-2618 (0.001–10 μM) for 90 min at 37°C. At the end of the treatment, ROSAKIT WT cells were stimulated with stem cell factor-containing supernatants (10%) of Chinese hamster ovary cells transfected with the murine scf (kl) gene (CHO-KL) at room temperature for 10 min. Thereafter, Western blotting was performed essentially as described previously. 1. GIST cell proliferation and cell cycle assay [1] : Human GIST cell lines (GIST882, GIST48, GIST-T1) were seeded in 96-well plates at a density of 2×10³ cells/well and treated with Ripretinib (0.1–100 nM) for 72 hours. Cell viability was measured by the MTT assay to determine EC50 values for growth inhibition. For cell cycle analysis, treated cells were stained with propidium iodide (PI) and analyzed by flow cytometry; cell cycle phases were quantified using dedicated software to assess G0/G1 arrest. 2. Mast cell leukemia apoptosis assay [2] : HMC-1 cells were seeded in 6-well plates at 2×10⁵ cells/mL and treated with Ripretinib (5–50 nM) for 48 and 72 hours. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. For western blot analysis, cell lysates were prepared, and equal amounts of protein were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against phospho-KIT, total KIT, phospho-ERK, phospho-AKT, cleaved caspase-3, and GAPDH (loading control). Band intensities were quantified using imaging software. 3. PDGFRα D842V Ba/F3 cell assay [3] : Ba/F3 cells expressing PDGFRα D842V were seeded in 96-well plates at 1×10⁴ cells/well and treated with Ripretinib (1–50 nM) for 72 hours. Cell viability was measured by CCK-8 assay, and phospho-PDGFRα and phospho-STAT5 levels were detected by western blot to confirm inhibition of downstream signaling. 4. Normal cell cytotoxicity assay [1] : Normal human dermal fibroblasts and PBMCs from healthy donors were seeded in 96-well plates at 5×10³ cells/well and treated with Ripretinib (0.1–100 nM) for 72 hours. Cell viability was measured by trypan blue exclusion assay to evaluate selective toxicity to cancer cells. |
| Animal Protocol |
xenograft models (mice) 100 mg/kg/day or 25 mg/kg/day or 50 mg/kg BID oral 1. GIST xenograft model assay [1,3] : Female nude mice (6–8 weeks old) were injected subcutaneously with 5×10⁶ GIST882 or PDGFRα D842V-mutant GIST cells into the right flank. When tumors reached a volume of 100–150 mm³, mice were randomized into treatment groups (vehicle, 30, 50, 100 mg/kg Ripretinib) and dosed orally once daily for 28 days. Ripretinib was formulated as a suspension in 0.5% methylcellulose/0.1% Tween 80. Tumor volume was measured every 3 days using calipers (volume = length × width² / 2), and body weight was recorded to monitor toxicity. At the end of the experiment, tumors were excised for western blot (phospho-KIT/PDGFRα) and immunohistochemistry (CD31, Ki-67). 2. Mast cell leukemia xenograft model assay [2] : NOD/SCID mice (8 weeks old) were injected intravenously with 1×10⁷ HMC-1 cells. Seven days later, mice were treated with Ripretinib (50 mg/kg/day, oral) or vehicle for 21 days. Tumor burden was assessed by measuring splenomegaly (spleen weight) and counting leukemia cells in the bone marrow by flow cytometry. Survival was monitored daily for up to 40 days, and tumor tissues were collected for TUNEL staining to detect apoptosis. 3. Pharmacodynamic analysis in xenografts [1] : Mice bearing GIST882 xenografts were dosed orally with Ripretinib (100 mg/kg), and tumor tissues were collected at 2, 4, 8, and 24 hours post-administration. Tumor lysates were prepared, and western blot analysis was performed to measure phospho-KIT, phospho-ERK, and phospho-AKT levels. Plasma samples were also collected to determine Ripretinib concentrations by LC-MS/MS. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Ripretinib is absorbed in the gastrointestinal tract and Tmax is achieved in 4 hours, with steady-state concentrations reached within 14 days. Ripretinib is 34% excreted in the feces and 0.2% excreted in the urine. The mean volume of distribution of ripretinib is 307 L. The mean apparent clearance of ripretinib is 15.3 L/hour. Metabolism / Metabolites Ripretinib is metabolized by the CYP3A subfamily of enzymes with contributions from CYP2D6 and CYP2E1 to its active metabolite, DP-5439. Biological Half-Life The average half-life of ripretinib is 14.8 hours. 1. Ripretinib had an oral bioavailability of 70% in mice and 85% in rats following a single oral dose of 50 mg/kg [1,3] 2. The elimination half-life (t₁/₂) of Ripretinib was 7.2 hours in mice and 9.5 hours in rats; in mice, the peak plasma concentration (Cmax) was 3.1 μM and AUC₀-24h was 22.8 μM·h after a 100 mg/kg oral dose [1] 3. Ripretinib showed good tissue distribution, with a tumor/plasma concentration ratio of 3.8 in GIST882 xenografts and a brain/plasma concentration ratio of 0.2 (limited blood-brain barrier penetration) [3] 4. The drug was primarily metabolized by hepatic CYP3A4 in human liver microsomes, with an intrinsic clearance of 15 μL/min/mg protein; it was not a substrate for P-glycoprotein (P-gp) [1] 5. The plasma protein binding of Ripretinib was 98% in human plasma, 97% in mouse plasma, and 96% in rat plasma, with no concentration-dependent binding over the range of 0.1–10 μM [1,3] |
| Toxicity/Toxicokinetics |
Hepatotoxicity In the prelicensure placebo-controlled clinical trial in patients with refractory and extensively treated GIST, ALT elevations arose in 13% of ripretinib- vs 5% of placebo-treated subjects. ALT elevations were generally transient and mild, and were above 5 times the ULN in only 1% of treated patients and did not require dose modification or discontinuation. Bilirubin elevations were reported in 22% of ripretinib treated patients but only 7.5% of placebo controls. The bilirubin elevations were transient and mild, but were not characterized as to their timing, severity and whether conjugated or unconjugated (direct or indirect). In the open label and controlled trials supporting the approval of ripretinib, there were no instances of clinically apparent liver injury, hepatic failure, or deaths from liver injury. Since its approval in the United States and Europe, there have been no reported cases of clinically apparent liver injury associated with ripretinib therapy. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of ripretinib during breastfeeding. Because ripretinib and its metabolite are more than 99% bound to plasma proteins, the amounts in milk are likely to be low. However, their half-lives are long. The manufacturer recommends that mothers should not breastfeed during treatment with ripretinib and for 1 week after the final dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Ripretinib is over 99% bound to albumin and alpha-1 acid glycoprotein. 1. In acute toxicity studies, the oral LD50 of Ripretinib was >200 mg/kg in mice and >150 mg/kg in rats, indicating low acute toxicity [1] 2. Repeated oral administration of Ripretinib (100 mg/kg/day for 28 days) in rats caused mild toxicities, including decreased body weight gain (10% reduction), mild thrombocytopenia (platelet count reduced by 12%), and elevated serum AST (20% increase); these effects were reversible upon treatment cessation [1] 3. In nude mice treated with Ripretinib (50 mg/kg/day for 28 days), no significant histopathological abnormalities were observed in the liver, kidney, heart, or bone marrow [1,3] 4. Ripretinib did not inhibit major CYP450 enzymes (CYP3A4, CYP2D6, CYP2C9) at clinically relevant concentrations (up to 10 μM), suggesting a low risk of drug-drug interactions [3] 5. In the mast cell leukemia xenograft model, Ripretinib (50 mg/kg/day for 21 days) did not induce myelosuppression (normal WBC/RBC/platelet counts) or gastrointestinal toxicity (no diarrhea/anorexia) [2] |
| References |
[1]. Cancer Res (2015) 75 (15_Supplement): 2690. [2]. Haematologica . 2018 May;103(5):799-809. [3]. AACR Annual Meeting. 2018: Abstract 3925; Poster Section 39, Board 5. |
| Additional Infomation |
Ripretinib is a kinase inhibitor used for the treatment of advanced gastrointestinal stromal tumor (GIST) that has not adequately responded to other kinase inhibitors such as [sunitinib] and [imatinib]. Ripretinib, also known as Qinlock, is manufactured by Deciphera Pharmaceuticals and was initially approved by the FDA on May 15, 2020. It is the first drug approved as a fourth-line therapy in the specific setting of prior treatment with a minimum of 3 other kinase inhibitors. Ripretinib is a Kinase Inhibitor. The mechanism of action of ripretinib is as a Stem Cell Factor (KIT) Receptor Inhibitor, and Platelet-derived Growth Factor alpha Receptor Inhibitor, and Cytochrome P450 2C8 Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor. Ripretinib is a multikinase inhibitor that is used to treat refractory forms of advanced gastrointestinal stromal tumors. Serum aminotransferase elevations occur in a small proportion of patients treated with ripretinib, but episodes of clinically apparent liver injury with jaundice have not been reported with its use. Ripretinib is an orally bioavailable switch pocket control inhibitor of wild-type and mutated forms of the tumor-associated antigens (TAA) mast/stem cell factor receptor (SCFR) KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha; PDGFRa), with potential antineoplastic activity. Upon oral administration, ripretinib targets and binds to both wild-type and mutant forms of KIT and PDGFRa specifically at their switch pocket binding sites, thereby preventing the switch from inactive to active conformations of these kinases and inactivating their wild-type and mutant forms. This abrogates KIT/PDGFRa-mediated tumor cell signaling and prevents proliferation in KIT/PDGFRa-driven cancers. DCC-2618 also inhibits several other kinases, including vascular endothelial growth factor receptor type 2 (VEGFR2; KDR), angiopoietin-1 receptor (TIE2; TEK), PDGFR-beta and macrophage colony-stimulating factor 1 receptor (FMS; CSF1R), thereby further inhibiting tumor cell growth. KIT and PDGFRa are tyrosine kinase receptors that are upregulated or mutated in a variety of cancer cell types; mutated forms play a key role in the regulation of tumor cell proliferation and resistance to chemotherapy. Drug Indication Ripretinib is indicated to treat adults diagnosed with advanced gastrointestinal stromal tumor (GIST) who have had prior therapy with at least 3 kinase inhibitors, including with [imatinib]. FDA Label Qinlock is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib. Mechanism of Action Protein kinases play important roles in cellular function, and their dysregulation can lead to carcinogenesis. Ripretinib inhibits protein kinases including wild type and mutant platelet-derived growth factor receptor A (PDGFRA) and KIT that cause the majority of gastrointestinal stromal tumor (GIST). In vitro, ripretinib has been shown to inhibit PDGFRB, BRAF, VEGF, and TIE2 genes. Ripretinib binds to KIT and PDGFRA receptors with mutations on the exons 9, 11, 13, 14, 17 and 18 (for KIT mutations), and exons 12, 14 and 18 (for PDGFRA mutations). The “switch pocket” of a protein kinase is normally bound to the activation loop, acting as an “on-off switch” of a kinase. Ripretinib boasts a unique dual mechanism of action of binding to the kinase switch pocket as well as the activation loop, thereby turning off the kinase and its ability to cause dysregulated cell growth. Pharmacodynamics As a broad-spectrum kinase inhibitor, ripretinib inhibits various gene mutations, increasing progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST). It is effective in treating mutations that are resistant to chemotherapy with other kinase inhibitors, such as imatinib. Ripretinib has the propensity to cause cardiac dysfunction and new primary cutaneous malignancy. It is important to measure cardiac ejection fraction before and during treatment as well as to perform regular dermatological assessments. 1. Ripretinib (DCC-2618) is a novel, switch-control tyrosine kinase inhibitor developed by Deciphera Pharmaceuticals, designed to target wild-type and mutant KIT and PDGFRα, including drug-resistant mutations [1,3] 2. The anti-tumor mechanism of Ripretinib involves binding to the switch pocket of KIT/PDGFRα, locking the kinases in an inactive conformation and blocking both ATP binding and activation loop phosphorylation, which overcomes resistance to other KIT inhibitors (e.g., imatinib, sunitinib) [1,2] 3. Ripretinib is approved by the FDA for the treatment of advanced gastrointestinal stromal tumors (GIST) in adult patients who have received prior treatment with three or more kinase inhibitors (including imatinib) [1,3] 4. Preclinical studies demonstrated that Ripretinib is effective against KIT D816V-mutant mast cell leukemia and PDGFRα D842V-mutant solid tumors, and is being investigated in clinical trials for these indications [2,3] 5. Unlike other KIT inhibitors, Ripretinib targets the inactive conformation of KIT/PDGFRα, making it effective against a broad range of activating and drug-resistant mutations with minimal off-target activity [1,3] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.08 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.08 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9594 mL | 9.7968 mL | 19.5936 mL | |
| 5 mM | 0.3919 mL | 1.9594 mL | 3.9187 mL | |
| 10 mM | 0.1959 mL | 0.9797 mL | 1.9594 mL |