flt3-itd

FLT3 ITD-IN-3 (Compound 19) is a potent inhibitor of FLT3-ITD, demonstrating efficacy against FLT3D835Y (IC50: 0.3 nM), FLT3 (IC50: 0.4 nM), and FLT3-ITD (IC50: 0.9 nM). It significantly inhibits FLT3 phosphorylation and effectively suppresses the proliferation of AML cells.

PDGFRα FLT3-ITD-IN-3 (Compound 18d) is a potent inhibitor of PDGFRα (IC50: 0.153 μM) and FLT3 (IC50: 0.004 μM), with potential applications in the study of acute myeloid leukaemia or chronic eosinophilic leukaemia.

PROTAC FLT-3 degrader 1 is a PROTAC FLT-3 degrader of internal tandem duplication (ITD) with an IC50 of 0.6 nM and exhibits anti-proliferative activity.

FLT3 ITD-IN-5 (Example 6) is an orally active inhibitor of both FLT3 and FLT3-ITD, exhibiting IC50 values of 0.088 nM and 0.348 nM, respectively. This compound is utilized in cancer research.

FLT3 ITD-IN-1 (Compound 1) is a highly potent inhibitor of FLT3 internal tandem duplications (FLT3-ITD) with IC50 values of 38.2 nM for FLT3 and 144.1 nM for FLT3-ITD, and shows exceptional antiproliferative activities against several acute myeloid leukemia cell lines [1].

FLT3 ITD-IN-4 (Compound 16) is a selective inhibitor of FLT3 internal tandem repeat mutations (FLT3-ITD) with an IC50 of 2.3 nM and is applicable for studying acute myeloid leukemia.

FLT3/ITD-IN-2 is a potent inhibitor of FLT3-ITD and is able to act on FLT3D835Y (IC50: 0.3 nM), FLT3 (IC50: 0.4 nM) and FLT3-ITD (IC50: 1.0 nM).FLT3/ITD-IN-2 effectively inhibits the phosphorylation of FLT3 and is able to effectively inhibit the proliferation of acute myeloid leukemia cells.

PDGFRα/FLT3-ITD-IN-1 are potent inhibitors of PDGFRα/FLT3, and their IC50 values are greater than 0.036 and 0.003 μM, respectively. PDGFRα/FLT3-ITD-IN-1 exhibits investigational potential in acute myeloid leukemia or chronic eosinophilic leukemia.

PDGFRα/FLT3-ITD-IN-2 is a potent inhibitor of PDGFRα (IC50>20 μM) and FLT3 (IC50: 0.004 μM). PDGFRα/FLT3-ITD-IN-2 has shown investigational potential in acute myeloid leukemia or chronic eosinophilic leukemia.

Antiproliferative Against-3 (comp 33) demonstrates significant activity against Hela (IC 50 = 0.21 µM), A549 (IC 50 = 0.39 µM), and MCF-7 (IC 50 = 0.33 µM) cell lines. Additionally, it induces apoptosis in a dose-dependent manner by arresting A549 cells in the G1 phase.

HM43239 is an orally active and selective FLT3 inhibitor with IC 50 s of 1.1 nM, 1.8 nM and 1.0 nM for FLT3 WT, FLT3 internal tandem duplication (ITD) and FLT3 D835Y kinases, respectively. HM43239 directly inhibits the kinase activity of FLT3 as a reversible Type I inhibitor and effectively modulates downstream p-STAT5 and p-ERK. HM43239 also demonstrated inhibition of SYK, JAK1 2 and TAK1. HM43239 inhibits the proliferation and induces the apoptosis of leukemic cells [1] [2] [3].

Quizartinib (AC220) is an inhibitor of FLT3 (Kd: 1.6 nM) and demonstrates high selectivity for FLT3 when tested against a panel of 227 additional kinases.

CCT241736 is an orally bioavailable dual FLT3/Aurora kinase inhibitor that also inhibits clinically relevant FLT3-resistant mutants including FLT3-ITD and FLT3, CCT241736, an advanced analog of CCT137690, is a preclinical development candidate for the treatment of human malignancies, and in particular AML in adults and children.

PF15 TFA, a PROTAC targeting FLT3 kinase and CRBN, exhibits selective degradation of FLT3-ITD with a DC50 of 76.7 nM. The compound potently suppresses proliferation in FLT3-ITD-positive cells, reduces phosphorylation levels of FLT3 and STAT5, and demonstrates inhibition of tumor growth in murine leukemia models [1].

FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity. FI-700 showed a potent IC(50) value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)-driven growth of Wt-FLT3-expressing cells. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. (Source: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4575-82.)

Abivertinib, also known as AC0010 and Avitinib, is a third-generation EGFR tyrosine kinase inhibitor and BTK Inhibitor that demonstrated clinical efficacy and manageable adverse events (AEs). Abivertinib inhibits cell proliferation, reduces colony-forming capacity, and induces apoptosis and cell cycle arrest in AML cells, especially those harboring FLT3-ITD mutations. Abivertinib was also found to be more sensitive than ibrutinib in treating AML. Abivertinib may be a promising novel agent for AML, with potential for combination treatment with HHT.

FLT3-IN-23 (compound 15), a potent inhibitor of FMS-like tyrosine kinase 3 (FLT3), exhibits an IC 50 value of 7.42 nM and demonstrates antiproliferative effects against BaF3 cells harboring diverse FLT3-TKD and FLT3-ITD-TKD mutations [1].

HDAC10-IN-2 (compound 10c) is a potent and highly selective HDAC10 inhibitor (IC50 = 20 nM) that regulates autophagy in aggressive FLT3-ITD positive acute myeloid leukemia cells [1].

G-749 hydrochloride is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays.

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor models. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing. (source: Invest New D......

CDDD11-8 is an orally administered, highly potent and selective CDK9 and FLT3-ITD inhibitor, with K i values of 8 nM and 13 nM, respectively. It effectively reduces the proliferation of leukemia cell lines, showing particular efficacy against those with the FLT3-ITD mutation [1] [2].

BIX02188 is a selective and potent MEK5 inhibitor that inhibits MEK5-induced apoptosis in cells expressing the oncogenic mutant FLT3-ITD.

FLT3-IN-14 is a potent inhibitor of FLT3, targeting FLT3-WT (IC50: 5.6 nM) and FLT3-ITD (IC50: 1.4 nM). It inhibits FLT3 (Y591) phosphorylation, arrests the cell cycle in the G1 phase, and induces apoptosis.

BSc5371 is a potent and irreversible FLT3 inhibitor (Kds: 1.3, 0.83, 1.5, 5.8, and 2.3 nM for mutant FLT3 D835H, FLT3 ITD D835V, FLT3 ITD F691L, FLT3-ITD, and wild type FLT3 wt).

HDAC10-IN-1 (compound 13b) is a potent and highly selective HDAC10 inhibitor (IC50 = 58 nM) that regulates autophagy in aggressive FLT3-ITD positive acute myeloid leukemia cells [1].

GTP-14564 is a novel tyrosine kinase inhibitor that also inhibits wt-FLT3 and ITD-FLT3. GTP-14564 inhibits the growth of interleukin-3-independent Ba/F1 expressing ITD-FLT3 at 3 μ m, whereas a 30-fold higher concentration of GTP-14564 is required to inhibit the FLT3 ligand-dependent growth (wt-FLT3) of Ba/F3 expressing wild-type FLT3. F3 expressing wild-type FLT3 (wt-FLT3).

Sorafenib N-oxide is an active metabolite of sorafenib , an inhibitor of Raf-1, B-RAF, and receptor tyrosine kinases. Sorafenib N-oxide inhibits FLT3 that contains the internal tandem duplication mutation (FLT3-ITD; Kd = 70 nM) and inhibits proliferation of MV4-11 acute myeloid leukemia (AML) cells expressing FLT3-ITD (IC50 = 25.8 nM). It is selective for AML cell lines containing FLT3-ITD over lines containing wild-type FLT3 (IC50s = 3.9-13.3 μM). Sorafenib N-oxide is also a linear-mixed inhibitor of the cytochrome P450 (CYP) isoform CYP3A4 (Ki = 15 μM in human liver microsomes).

SEL24-B489 is a highly effective and orally bioavailable compound that acts as a robust, type I inhibitor of both PIM and FLT3-ITD. It exhibits exceptional binding affinity with K d values of 2 nM for PIM1, 2 nM for PIM2, and 3 nM for PIM3.

FLT3-IN-6 is a potent and selective inhibitor of FLT3-ITD [FLT3 mutation], with an IC50 of 1.336 nM.

FLT3 TrKA-IN-1 is a potent dual kinase inhibitor that targets FLT3 (IC50: 43.8 nM), FLT3-ITD (IC50: 97.2 nM), FLT3-TKD (IC50: 92.5 nM), and TrKA (IC50: 23.6 nM). FLT3 TrKA-IN-1 shows potential for acute myeloid leukaemia (AML) studies.

PROTAC FLT3/CDK9 degrader-1, a potent dual degrader of FLT3 and CDK9, effectively induces apoptosis and targets protein degradation of FLT3 and CDK9. This compound holds research potential for FLT3-ITD mutated AML [1].

LT-540-717 (compound 32), a potent FLT3 inhibitor (IC50=0.62 nM), exhibits antiproliferative activity and effectively inhibits various acquired FLT3 mutations, including FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (D835Y), and FLT3 (D835V), indicating its potential as an anti-AML agent [1].

MELK-8a (NVS-MELK8a) is a potent and selective inhibitor of maternal embryonic leucine zipper kinase (MELK), with an IC50 of 2 nM and an IC50 of 0.42 μM in cellular assays. MELK is crucial in regulating mitosis in cancer cells.

Antiproliferative agent-30 (Compound 8g) exhibits broad-spectrum antiproliferative activity, with IC50 values of 0.054 nM, 0.008 nM, and 0.144 nM against HCT-116, K562, and MV-4-11 cancer cell lines, respectively. It inhibits tubulin assembly, FLT3, and Abl1 kinases and shows vascular-disrupting capabilities. Additionally, it displays an anticancer effect against acute myeloid leukemia (AML) with FLT3-ITD-TKD mutations [1].

HP1328 is a highly effective inhibitor of FLT3 receptor tyrosine kinase with a specific focus on FLT3/ITD mutation. It belongs to the benzoimidazole scaffold-based compound family. Significantly reducing the leukemia burden, HP1328 effectively extends the survival of mice afflicted with FLT3/ITD leukemia [1].

AC-4-130, a powerful inhibitor of the SH2 domain of STAT5, effectively hinders STAT5 activation, dimerization, nuclear translocation, and transcription of genes reliant on STAT5. This compound directly binds to STAT5, ultimately leading to cell cycle arrest and apoptosis in FLT3-ITD-driven leukemic cells. AC-4-130 exhibits notable anti-cancer properties and effectively suppresses abnormal STAT5 activity in acute myeloid leukemia (AML), making it a promising therapeutic option [1].

Wu-5 is a potent USP10 inhibitor that inhibits FLT3 and AMPK pathways, promoting the breakdown of FLT3-ITD and inducing apoptosis.

FLT3-IN-21 (compound LC-3), a potent FLT3 inhibitor with an IC50 value of 8.4 nM, induces apoptosis, arrests the cell cycle in the G1 phase, and effectively inhibits the proliferation of FLT3-ITD-positive AML cells MV-4-11 with an IC50 of 5.3 nM. In murine models, a daily dose of 10 mg kg FLT3-IN-21 markedly inhibited tumor growth in the MV-4-11 xenograft model, achieving a tumor growth inhibition (TGI) of 92.16% [1].

FLT3-IN-20 (compound 34f) is a potent FLT3 inhibitor with IC50 values of 1 nM for FLT3-D835Y and 4 nM for FLT3-ITD. It shows anti-proliferative effects on FLT3-ITD-positive AML cell lines, with IC50s of 7 nM in MV4-11, 9 nM in MOLM-13, and 4 nM in a MOLM-13 variant harboring the FLT3-ITD-D835Y mutation. FLT3-IN-20 is utilized in cancer research [1].

PF15, a selective FLT3-ITD degrader, serves as a PROTAC (proteolysis targeting chimera) tethering ligands for FLT3 kinase and CRBN. It exhibits a degradation concentration 50 (DC50) of 76.7 nM and notably impedes the proliferation of FLT3-ITD-positive cells. PF15 also reduces phosphorylation levels of FLT3 and STAT5 and demonstrates efficacy in inhibiting tumor growth in mouse models, suggesting potential applications in leukemia research [1].

HDAC10-IN-2 hydrochloride (compound 10c) is a highly potent and selective HDAC10 inhibitor with an IC50 of 20 nM, influencing autophagy in aggressive FLT3-ITD positive acute myeloid leukemia cells [1].

SKLB4771 (FLT3-IN-1) is a novel potent and selective Flt3 inhibitor.

JH-IX-179 is a novel type I ATP competitive and highly selective FLT3 inhibitor. JH-IX-179 is much more selective for FLT3 and FLT3 mutants than for Kronani. In addition, JH-IX-179 showed little human serum protein binding and effectively inhibited autoph

Pomalidomide-C5-Dovitinib (compound 2) is a PROTAC linking Pomalidomide and Dovitinib via a CRBN connector, exhibiting potent antiproliferative activity in FLT3-ITD+ acute myeloid leukemia (AML) cells. It promotes ubiquitin-proteasome-dependent degradation of FLT3-ITD and KIT proteins, thereby inhibiting their downstream signaling pathways and presenting research potential in FLT3-ITD+ AML [1].

Tandutinib (CT53518) (MLN518, CT53518), an effective FLT3 antagonist (IC50: 0.22 μM), can also inhibit c-Kit and PDGFR, 15-20 fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR, and KDR.

BPR1J-340 is a potent and selective FLT3 inhibitor with potential anticancer activity. BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD(+) AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD(+) AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy.

Tuspetinib (HM43239) hydrate is a selectively active FLT3 inhibitor for oral administration, demonstrating IC₅₀ values of 1.1 nM for FLT3 WT, 1.8 nM for FLT3 internal tandem duplication (ITD), and 1.0 nM for FLT3 D835Y kinases. As a reversible type I inhibitor, it suppresses FLT3 kinase activity and influences signaling pathways including p-STAT5, p-ERK, SYK, JAK1 2, and TAK1. Additionally, Tuspetinib hydrate inhibits leukemic cell proliferation and triggers apoptosis [1] [2] [3].