flt3-in-4

FLT3-IN-4 (FLT3 inhibitor 9u) is a potent and orally effective Fms-like tyrosine receptor kinase 3 (FLT3; IC50=7 nM) inhibitor ,for treating acute myelogenous leukemia.

FLT3-IN-41 is a potent FLT3 inhibitor with IC50 values of 3.16 nM for human FLT3-ITD and 294.7 nM for FLT3-WT. It suppresses the STAT5, Akt, and Erk signaling pathways by binding to the ATP pocket of FLT3-ITD and FLT3-WT, forming hydrogen bonds with hinge region residues and Phe830. FLT3-IN-41 induces G2/M phase arrest and promotes apoptosis in FLT3-ITD positive acute myeloid leukemia cells, demonstrating significant antiproliferative activity. This compound serves as an important tool for the study of acute myeloid leukemia.

FLT3-IN-40 (compound 1) is a type I ATP-competitive FLT3 inhibitor with an IC50 of 16.26 nM. It reduces the autophosphorylation levels of FLT3 and the phosphorylation levels of downstream ERK. FLT3-IN-40 exhibits antiproliferative activity, cell cycle regulation, and apoptosis induction. It is applicable in research related to acute myeloid leukemia.

JI6 (JAK3 Inhibitor VI) is a potent, selective and orally active FLT3 inhibitor. JI6 exhibits IC50s of ∼40, 8, and 4 nM for FLT3-WT, FLT3-D835Y, and FLT3-D835H, respectively. JI6 also inhibits c-Kit and JAK3, with IC50s of ∼500 and ∼250 nM, respectively. JI6 has research value in acute myeloid leukemia.

JAK3-IN-14 is a potent, selective and orally active FLT3 inhibitor, with IC50s of ∼40, 8, and 4 nM for FLT3-WT, FLT3-D835Y, and FLT3-D835H, respectively.

Cediranib (AZD2171) (AZD2171) is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro, also inhibits Flt1/4 (IC50: 5 nM/≤3 nM), similar activity against PDGFRβ and c-Kit, selective more for VEGFR than PDGFR-α (36-fold), CSF-1R (110-fold), and Flt3 (1000-fold) in HUVEC cells.

HPK1-IN-2 (Thieno[2,3-b]pyridin-6(7H)-one, 4-amino-5-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-HPK1-IN-2) is a potent and orally active inhibitor of hematopoietic progenitor kinase-1 (HPK1; IC50<0.05 μΜ). It also inhibits Lck (0.05 μΜFlt3 (IC50<0.05 μΜ) kinase activities with antitumor activity.

FLT3-IN-10 (2-Oxazolamine, 5-(4-fluorophenyl)-N-phenyl-) (compound 7c) is a potent inhibitor of FMS-like tyrosine kinase 3 (FLT3). FLT3-IN-10 shows the potential for the treatment of FLT3-mutated acute myeloid leukemia (AML).

TAS05567 is a potent, highly selective, and ATP-competitive Syk inhibitor (IC50: 0.37 nM), showing >70% inhibition of Syk and four other kinases [FLT3 (IC50: 10 nM), JAK2 (IC50: 4.8 nM), KDR (IC50: 600 nM), RET (IC50: 29 nM)] in a panel of 192 kinases.

FLT3/HDAC-IN-1 is a dual inhibitor targeting FLT3 and HDAC, with IC50 values of 30.4 nM for FLT3 and 52.4, 14.7 nM for HDAC1/3, respectively. It induces apoptosis in MV-4-11 cells and exhibits antiproliferative effects against BaF3 cells transformed by FLT3 mutations. FLT3/HDAC-IN-1 is useful for research on refractory solid tumors and hematological malignancies.

Multi-kinase inhibitor 4 (compound 14) serves as an orally effective inhibitor targeting FLT1, KDR, FLT3, FLT4, PDGFRα, and PDGFRβ, exhibiting IC50 values of 1.97 nM, 1.04 nM, 0.33 nM, 1.44 nM, 0.18 nM, and 0.89 nM respectively. This compound plays a crucial role in cancer research.

IRAK1/4/pan-FLT3 Kinase-IN-1 (Compound 31) is a potent inhibitor of IRAK1, IRAK4, and FLT3 kinases, demonstrating IC50 values of 5 nM for IRAK1, 0.6 nM for IRAK4, and less than 0.5 nM for FLT3. It exhibits favorable pharmacokinetic properties and holds promise for research in acute myeloid leukemia, with survival extension effects comparable to Gilteritinib.

FGFRs-IN-1 (Compound A16) is an orally active inhibitor targeting FGFR1/2/3/4, with IC50 values of 2.3, 7, 11, and 163 nM respectively. It also inhibits VEGFR1/2/3, Abl, and Flt3, with IC50 values of 61, 176, 112, 26, and 353 nM. The compound shows weak inhibition of CYP enzymes. FGFRs-IN-1 reduces the expression of α-SMA and collagen I, and it inhibits epithelial-mesenchymal transition (EMT) in A549 cells stimulated by TGF-β1. Additionally, FGFRs-IN-1 demonstrates anti-inflammatory activity in mouse models of lung fibrosis induced by Bleomycin and liver fibrosis induced by CCl4.

IRAK1/4/pan-FLT3 Kinase-IN-2 (compound 27) is a potent dual inhibitor of IRAK1/4 and FLT3 with IC50 values of 10 nM, 0.7 nM, and < 0.5 nM, respectively. This compound enhances survival in mice models of acute myeloid leukemia.

PROTACFLT3/CHK1 Degrader-1 is a PROTAC agent targeting FLT3 and CHK1, with DC50 values of 5.88 nM (FLT3) and 4.17 nM (CHK1). It inhibits the phosphorylation of downstream signaling effectors STAT5(Tyr694), AKT(Ser473), and ERK(Tyr204) of FLT3, reduces c-Myc protein levels, and maintains p53 protein expression. Additionally, PROTACFLT3/CHK1 Degrader-1 induces apoptosis in MV-4-11 cells and demonstrates significant antitumor activity in mice with MV-4-11 xenografts. This compound is applicable in acute myeloid leukemia (AML) research.

LY2784544(Gandotinib (LY2784544)) is a potent JAK2 inhibitor (IC50: 3 nM), effective in JAK2V617F(Ki: 0.245 nM). The selectivity is higher 8- and 20-fold than JAK1 and JAK3.

AC-4-130 is a direct STAT5 SH2 domain inhibitor that can disrupt STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription, inducing cell cycle arrest and apoptosis in leukemia cells, and can be used for the study of acute myeloid leukemia (AML).

Luxeptinib (CG-806) is a novel pan-FLT3/pan-BTK inhibitor that is administered orally. It exhibits potent and reversible inhibition of these enzymes, acting through a non-covalent mechanism. Luxeptinib effectively induces cell cycle arrest, apoptosis, or autophagy in acute myeloid leukemia cells [1][2][3][4].

RET-IN-4 is a highly effective and specific RET inhibitor that can be administered orally. It demonstrates remarkable potency, with IC50 values of 1.29 nM, 1.97 nM, and 0.99 nM for inhibiting RET variants including RET (WT), RET (V804M), and RET (M918T), respectively. Moreover, RET-IN-4 exhibits superior selectivity towards kinases JAK2 (IC50 of 4.4 nM) and FLT3 (IC50 of 30.8 nM). Additionally, RET-IN-4 possesses pronounced anticancer properties.

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.

JAK2/FLT3-IN-1 (TFA) is an orally active dual inhibitor of JAK2 (IC50: 0.7 nM) and FLT3 (IC50: 4 nM) that demonstrates anticancer effects, also affecting JAK1 (IC50: 26 nM) and JAK3 (IC50: 39 nM).

Antiproliferative Agent-34 (Compound A14), a multitarget kinase inhibitor, demonstrates IC50 values of 177 nM for EGFR L858R/T790M and 1567 nM for EGFR WT. Additionally, it inhibits JAK2, ROS1, FLT3, FLT4, and PDGFRα with respective IC50s of 30.93 nM, 106.90 nM, 108.00 nM, 226.60 nM, and 42.53 nM. In normoxic conditions, it suppresses the proliferation of H1975 and HCC827 cells with IC50 values below 40 nM, while under hypoxic conditions, its potency increases 4-6 fold, yielding IC50 values less than 10 nM [1].

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].