STAT5 Inhibitor

QL-1200186 is a selective, orally active, allosteric inhibitor targeting the tyrosine kinase TYK2 pseudokinase domain JH2 (IC₅₀=0.06 nM, TYK2 JH2), with 164-fold selectivity over TYK1 JH2 (IC₅₀=9.85 nM，TYK1 JH2). QL-1200186 first stabilizes the TYK2 JH2 conformation, inhibits the activity of the JH1 catalytic domain, and blocks the IFNα, IL-12/IL-23-mediated JAK-STAT signaling pathway. QL-1200186 can inhibit the production of Th1/Th17 cell-related cytokines (such as IFNγ, IL-23), reduce immune cell activation, and has no significant effect on JAK1/2/3 kinase activity. QL-1200186 can significantly improve skin inflammation in the Imiquimod (HY-B0180)-induced psoriasis mouse model and reduce the Psoriasis Area and Severity Index (PASI) score. QL-1200186 can be used in the study of autoimmune diseases such as psoriasis and systemic lupus erythematosus (SLE).

CMD178 TFA is a lead peptide that consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/s IL-2Rα signaling and inhibits T_reg cell development.

Ibrutinib-MPEA is an orally active, blood-brain barrier permeable inhibitor of BTK and STAT5. As a derivative of Ibrutinib (HY-10997) conjugated with a PROTAC linker, Ibrutinib-MPEA allows the synthesis of a series of PROTAC molecules. Ibrutinib-MPEA significantly reduces the proliferation of neoplastic mast cells and primary mastocytoma cells by inducing apoptosis and inhibiting IgE-dependent histamine release. Ibrutinib-MPEA is applicable to the research of canine mast cell tumors, cerebral ischemia/reperfusion injury in diabetic mice, and neuroinflammation-related diseases.

Ritlecitinib (PF-06651600) tosylate is a highly selective, orally active, irreversible covalent JAK3 inhibitor (IC₅₀=33 nM) without inhibitory activity towards JAK1, JAK2, and TYK2 (IC₅₀ >10 μ M). Ritlecitinib tosylate rapidly inactivates the JAK3 kinase, and blocks signaling and downstream STAT phosphorylation mediated by common gamma chain cytokines such as IL-2 and IL-15. Ritlecitinib tosylate can inhibit Th1/Th17 cell differentiation and function, and effectively suppress preclinical animal models such as alopecia areata, adjuvant-induced arthritis (AIA), and experimental autoimmune encephalomyelitis (EAE).

Patiromer is an orally active, selective and non-absorbable intestinal potassium (K⁺) polymer binder that reversibly binds potassium ions in exchange for calcium (Ca²⁺). Patiromer can rapidly and continuously reduce serum potassium levels, maintain a normal blood potassium state, and reduce serum aldosterone levels. Patiromer also increases fecal potassium excretion. Patiromer is mainly used in the study of hyperkalemia associated with diseases such as chronic kidney disease, diabetes, and heart failure, and is particularly suitable for improving renin-angiotensin-aldosterone system inhibitor (RAASi) therapy.

CT1113 is a selective, orally active USP25/USP28 inhibitor. CT1113 inhibits cancer cell proliferation, induces apoptosis, and causes G2/S phase cell cycle arrest. CT1113 reduces the levels of total BCR-ABL1, phosphorylated BCR-ABL1, total STAT5, and phosphorylated STAT5, but does not alter the mRNA level of BCR-ABL1. CT1113 is applicable to research related to pancreatic cancer, colon cancer, and acute leukemia.

UC-514321, a structural analog of NSC370284 with higher activity, directly targets STAT3/5 and represses TET1 expression, but not TET2 or TET3. UC-514321 has the potential to treat acute myeloid leukemia (AML) both in vitro and in vivo, with low toxicity.

XOMA-213 (LFA-102; X213) is a human monoclonal antibody (mAb) targeting the prolactin receptor (PRLR), with a K_d value of 2 nM against the human target. XOMA-213 blocks PRL-induced cell proliferation and inhibits the activation of multiple PRLR ligands, including PRL and human growth hormone (hGH). XOMA-213 suppresses PRL-induced phosphorylation of Stat5, Akt and ERK1/2 in cells. XOMA-213 induces tumor regression, delays disease progression, and inhibits PRLR signaling as well as tumor growth. XOMA-213 can be used in research related to breast cancer.

Pimozide-d₄ is a deuterium labeled Pimozide. Pimozide is a dopamine receptor antagonist, with K_is of 1.4 nM, 2.5 nM and 588 nM for dopamine D2, D3 and D1 receptors, respectively, and also has affinity at α1-adrenoceptor, with a K_i of 39 nM; Pimozide also inhibits STAT3 and STAT5.

PF15 TFA is an orally active FLT3-ITD PROTAC degrader with a DC₅₀ of 76.7 nM and an IC₅₀ of 36 nM against FLT3-ITD. PF15 TFA induces FLT3-ITD protein degradation, thereby downregulating its phosphorylation level. PF15 TFA inhibits the proliferation of FLT3-ITD-positive cells and reduces the phosphorylation level of STAT5, a downstream molecule of FLT3-ITD. PF15 TFA exhibits efficacy in in vivo xenograft models of acute myeloid leukemia and prolongs survival. PF15 TFA can be used for the research of acute myeloid leukemia.

Stafia-1-dipivaloyloxymethyl ester (compound 27, 0-200 μM) decreases pSTAT5a expression significantly, and has no obvious inhibition on pSTAT5b.

IMC-EB10 (LY3012218) is an anti-FLT3 monoclonal antibody. IMC-EB10 binds to FLT3 with high affinity (K_d = 158 pM) and blocks the binding of FLT3 ligand to FLT3 (IC₅₀ ≈ 10 nM), thereby inhibiting MAPK, STAT5, and PI3K/Akt signaling in leukemia cells. IMC-EB10 can enhance the anti-leukemic effect of Methotrexate (HY-14519) and inhibit leukemias expressing wild-type or ITD-mutated FLT3 receptors. IMC-EB10 prolongs the survival of acute lymphoblastic leukemia (ALL) cells and primary leukemia samples and reduces engraftment in non-obese diabetic/severe combined immunodeficiency patients. IMC-EB10 is indicated for leukemia research.

TAVO101 is a humanized anti-TSLP antibody with an EC₅₀ of 0.19 nM against hTSLP. TAVO101 inhibits STAT5 activation and CCL17 release. TAVO101 carries Fc region mutations that enhance its binding to FcRn while reducing its binding to FcγRI, FcγRIIIA and C1q, thereby attenuating effector functions. TAVO101 reduces the levels of inflammatory markers, cell infiltration and histopathological damage in preclinical models of asthma, psoriasis and atopic dermatitis. TAVO101 can be used for research related to asthma, psoriasis and atopic dermatitis.

CMD178 is a lead peptide that consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/s IL-2Rα signaling and inhibits T_reg cell development.

Ritlecitinib (PF-06651600) malonate is a highly selective, orally active, irreversible covalent JAK3 inhibitor (IC₅₀=33 nM) without inhibitory activity towards JAK1, JAK2, and TYK2 (IC₅₀ >10 μ M). Ritlecitinib malonate rapidly inactivates the JAK3 kinase, and blocks signaling and downstream STAT phosphorylation mediated by common gamma chain cytokines such as IL-2 and IL-15. Ritlecitinib malonate can inhibit Th1/Th17 cell differentiation and function, and effectively suppress preclinical animal models such as alopecia areata, adjuvant-induced arthritis (AIA), and experimental autoimmune encephalomyelitis (EAE).

WYE-151650 is a selective JAK-3 inhibitor. WYE-151650 suppresses IL-2-induced STAT-5 phosphorylation and cell proliferation mediated by JAK-3. WYE-151650 is promising for research of autoimmune diseases.

PF15 is an orally active FLT3-ITD PROTAC degrader with a DC₅₀ of 76.7 nM and an IC₅₀ of 36 nM against FLT3-ITD. PF15 induces FLT3-ITD protein degradation, thereby downregulating its phosphorylation level. PF15 inhibits the proliferation of FLT3-ITD-positive cells and reduces the phosphorylation level of STAT5, a downstream molecule of FLT3-ITD. PF15 exhibits efficacy in in vivo xenograft models of acute myeloid leukemia and prolongs survival. PF15 can be used for the research of acute myeloid leukemia.

BCR-ABL degrader 1 is a hydrophobic tag degrader with GNF‑2 (HY-11007) as the ligand and Boc₂His (HY-185595) as the hydrophobic tag. BCR-ABL degrader 1 mediates the degradation of BCR‑ABL with a DC₅₀ of 19.9 μM. BCR-ABL degrader 1 induces the degradation of BCR-ABL fusion protein via the ubiquitin-proteasome pathway, a process involving Hsp70 and Hsp90. BCR-ABL degrader 1 downregulates p‑STAT5 and p‑SHP2, the downstream signaling molecules of BCR‑ABL. BCR-ABL degrader 1 can be used in the research of chronic myeloid leukemia.

MA191 is a FLT3 PROTAC degrader. MA191 targets and degrades mutant FLT3-ITD protein by recruiting the VHL E3 ligase in a manner dependent on ubiquitination and BIM, thereby blocking aberrant downstream MAPK/STAT5 signaling pathways and inducing apoptosis. MA191 can be used in research related to acute myeloid leukemia.

JAK2-IN-18 (Compound example1) is a selective JAK2 inhibitor. JAK2-IN-18 can inhibit JAK-STAT signaling and shows an IC₅₀ of <100 nM for pSTAT5 in HEL9217 cells. JAK2-IN-18 can inhibit the proliferation of abnormally proliferating myeloid cells and can be used for the research of myeloproliferative disorders, such as essential thrombocythemia.