RET Inhibitor

Zeteletinib (BOS-172738; DS-5010) hemiadipate is an orally active, selective RET kinase inhibitor with nanomolar potency against RET and >300-fold selectivity against VEGFR2. Zeteletinib hemiadipate shows exquisite potency for the wild type RET, RET^V804M/L gatekeeper mutants, and the most common oncogenic RET mutation M918T. Zeteletinib hemiadipate has potent antitumor activity.

RET-IN-4 is a potent, selective and orally active RET inhibitor with IC₅₀s of 1.29 nM, 1.97 nM, and 0.99 nM for RET (WT), RET (V804M), and RET (M918T), respectively. RET-IN-4 exhibits better kinases selectivity against JAK2 (IC₅₀ of 4.4 nM) and FLT3 (IC₅₀ of 30.8 nM). RET-IN-4 has anticancer effects.

CLM3, a pyrazolopyrimidine derivative, is a multiple tyrosine kinase inhibitor. CLM3 shows antiproliferative and proapoptotic activity on endothelial and cancer cells, synergistically enhanced by SN38 (HY-13704). These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signaling pathways.

RET-IN-15 is a rearranged during transfection (RET) kinase inhibitor extracted from patent WO2021115457A1 compound 51. RET-IN-15 can be used for the research of cancer.

LRRK2-IN-17 (Compound 6) is an orally active LRRK2 inhibitor (IC₅₀: 3.5 and 3.3 nM for WT and G2019S, respectively). LRRK2-IN-17 inhibits RET kinase (IC₅₀: 59 nM). LRRK2-IN-17 can be used in cancer and Parkinson's disease (PD) research.

Lenvatinib-d₅ is the deuterium labeled Lenvatinib. Lenvatinib (E7080) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFR, KIT, and RET, shows potent antitumor activities.

Lenvatinib-¹⁵N,d₄ is ¹⁵N and deuterated labeled Lenvatinib (HY-10981). Lenvatinib (E7080) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFR, KIT, and RET, shows potent antitumor activities.

RET-IN-6 is a potent RET (rearranged during transfection) inhibitor with an IC₅₀ of 4.57 nM (CN113461670A, compound 321).

Soxataltinib (example 7) is a potent inhibitor of RET-kinase, with the IC₅₀ of 0.601 nM. Soxataltinib plays an important role in cancer research.

PLM-101 is an orally available anticancer agent targeting FLT3 and RET with inhibitory activity against acute myeloid leukemia cells. PLM-101 inhibits RET, thereby inducing autophagic degradation of FLT3; and it inhibits the PI3K and Ras/ERK pathways, resulting in anti-leukemia activity. PLM-101 has anti-tumor efficacy in a mouse MV4-11 flank xenograft model (dose: 3, 10 mg/kg; po) and an allogeneic xenograft mouse model (dose: 40 mg/kg; po).

RET-IN-29 (Compound 8W) is a selective RET kinase inhibitor. RET-IN-29 exhibits inhibitory potency against the BaF3 cells harboring CCDC6-RET^V804M mutation with an IC₅₀ value of 0.715 μM. RET-IN-29 is promising for research of non-small cell lung cancer (NSCLC).

RET-IN-20 is a potent RET inhibitor with an IC₅₀ value of 13.7 nM. RET-IN-20 decreases the expression of p-Ret, p-Shc protein. RET-IN-20 induces apoptosis. RET-IN-20 shows antiproliferative and anti-tumor activity.

CDD-2211 is a STK33 inhibitor, with a K_d of 0.018 nM and an IC₅₀ of 5 nM. CDD-2211 has relatively weak inhibitory effects on off-target kinases, with IC₅₀ values of 115 nM for CLK1, 48 nM for CLK2, 187 nM for CLK4, and 78 nM for RET. CDD-2211 can be used for the study of contraception.

RET-IN-16 is a potent and selective RET inhibitor with IC₅₀s of 3.98 nM, 8.42 nM, 15.05 nM, 7.86 nM, 5.43 nM and 8.86 nM for RET(WT), RET(M918T), RET(V804L), RET(V804M), RET-CCDC6 and RET-KIF5B, respectively. RET-IN-16 has anticancer effects.

GR2-128 is a dual inhibitor targeting MLK3 and NAMPT with IC₅₀ values of 84 nM and 14 nM, respectively. GR2-128 inhibits downstream JNK/c‑Jun signaling and reduces NAD⁺ levels. GR2-128 exhibits antiproliferative and pro-apoptotic activities in triple-negative breast cancer cells without significant toxicity to normal cells. GR2-128 suppresses tumor growth, reduces macrophage and neutrophil infiltration, and increases tumor T-cell markers in a syngeneic mouse model, and can be used for triple-negative breast cancer research.

RET-IN-24 (Compound 26) is a selective RET tyrosine kinase inhibitor with antitumor activity.

RET-IN-1 is a RET kinase inhibitor extracted from patent WO2018071447A1, Compound Example 552, has IC_50s of 1 nM, 7 nM, and 101 nM for RET (WT), RET (V804M) , and RET (G810R), respectively .

RET-IN-23 (compound 17) is a potent and orally active RET inhibitor with IC₅₀ values of 1.32, 2.50, 6.54, 1.03, 1.47 nM for RET-WT, RET-CCDC6, RET-V804L, RET-V804M, RET-M918T, respectively. RET-IN-23 shows anti-tumor activity.

RET/TRKA-IN-1 (Compound 13) is a dual inhibitor for RET (IC₅₀=0.375 µM) and TRKA. RET/TRKA-IN-1 inhibits cell viability of LC-2 and KM12, with GI₅₀ of 0.72 and 0.25 μM. RET/TRKA-IN-1 arrests the cell cycle at G1 phase.

RET-IN-25 (compound 6b) is a RET kinase inhibitor with anticancer activity. RET-IN-25 inhibits medullary thyroid carcinoma (MTC) with IC₅₀s of 3.6 μM (3 days) and 3.0 μM (6 days) against TT(C634R) MTC.