FLT3/ITD-IN-1 (Compound 1) is a highly potent inhibitor of FLT3 internal tandem duplications (FLT3-ITD). It exhibits remarkable inhibitory effects against FLT3 and FLT3-ITD, with impressive IC50 values of 38.2 nM and 144.1 nM, respectively. Moreover, FLT3/ITD-IN-1 shows exceptional antiproliferative activities against several acute myeloid leukemia cell lines [1].

ITD-1 is a potent and highly selective TGFβ pathway inhibitor.

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.

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

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].

PHI-101, an orally active FLT3 inhibitor, effectively overcomes resistance associated with numerous drug-resistant mutations. It potently suppresses both single activating FLT3 mutations (ITD or TKD mutants) and inhibits double (ITD/D835Y or ITD/F691L) as well as triple (ITD/D835Y/F691L) resistance mutations. This compound shows promise for investigation in the context of relapsed or refractory acute myeloid leukemia (AML) [1].

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).

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

Desmorpholinyl Quizartinib-PEG2-COOH is a compound featuring an FLT-3 ligand and a PEG-based PROTAC linker. It is employed in the synthesis of PROTAC FLT-3 degrader 1, which serves as a degrader for the FLT-3 internal tandem duplication (ITD) through PROTAC technology. The degrader exhibits an IC50 of 0.6 nM.

HP1142 is a highly effective and specific inhibitor targeting the FLT3 receptor tyrosine kinase, with a particular affinity for its mutant variant FLT3/ITD. It exhibits a benzoimidazole scaffold-based structure, making it a promising compound for investigating and studying the FLT3/ITD mutation in the context of leukemia research [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.)

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].

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

HDAC10-IN-1 (compound 13b) is a potent and highly selective inhibitor of HDAC10 (IC 50 = 58 nM) that regulates autophagy in aggressive FLT3-ITD positive acute myeloid leukemia cells [1].

FLT3/TrKA-IN-1 is a potent FLT3/TrKA dual kinase inhibitor, capable of acting on 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 has potential for acute myeloid leukaemia (AML) studies.

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].

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].

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].

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].

Antiproliferative agent-30 (Compound 8g) demonstrates 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 as well as FLT3 and Abl1 kinases and exhibits vascular-disrupting capabilities. Additionally, it exerts an anticancer effect against acute myeloid leukemia (AML) with FLT3-ITD-TKD mutations [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].

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.

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 an HDAC10 inhibitor with high potency and selectivity, exhibiting an IC50 of 20 nM. It influences autophagy in aggressive FLT3-ITD positive acute myeloid leukemia cells [1].

FLT3-IN-21 (compound LC-3), a potent FLT3 inhibitor with an IC50 value of 8.4 nM, induces apoptosis and arrests the cell cycle in the G1 phase. It 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, demonstrating IC50 values of 1 nM for FLT3-D835Y and 4 nM for FLT3-ITD. It exhibits anti-proliferative effects on FLT3-ITD-positive AML cell lines, with IC50s of 7 nM in MV4-11 and 9 nM in MOLM-13, as well as 4 nM in a MOLM-13 variant harboring the FLT3-ITD-D835Y mutation. FLT3-IN-20 is utilized in cancer research [1].