PAN-4

Gimeracil (Gimestat) is a competitive, reversible inhibitor of dihydropyrimidine dehydrogenase.

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.

Pan-KRAS-IN-4 (compound 5) is a potent KRAS inhibitor, demonstrating IC50 values of 0.37 nM for Kras G12C and 0.19 nM for Kras G12V [1].

Trk-IN-4 (PF-6683324) is a potent pan-Trk inhibitor with IC50 = 1.1~2.6 nM for TrkA TrkB TrkC and antinociceptive effects. It is also a selective type II PTK6 inhibitor with IC50 = 76 nM and has antitumor effects.

Velpatasvir (GS-5816), also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. GS-5816 has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

Dactolisib (BEZ235) is an orally bioavailable inhibitor of PI3K and mTOR, with IC50 values of 4 nM for p110α, 5 nM for p110γ, 7 nM for p110δ, 75 nM for p110β, and 20.7 nM for mTOR.

Quisinostat (JNJ-26481585) (JNJ-26481585) is a novel second-generation HDAC inhibitor with highest potency for HDAC1 with IC50 of 0.11 nM, modest potent to HDACs 2, 4, 10, and 11; greater than 30-fold selectivity against HDACs 3, 5, 8, and 9 and lowest potency to HDACs 6 and 7.

FIIN-2, an irreversible, pan-FGFR inhibitor, inhibits FGFR1 2 3 4 with IC50 of 3.09 nM, 4.3 nM, 27 nM and 45.3 nM, respectively.

LJI308 is a potent, and pan-RSK (p90 ribosomal S6 kinase) inhibitor with IC50 of 6 nM, 4 nM, and 13 nM for RSK1, RSK2, and RSK3, respectively.

AMG410 is a non-covalent, bimodal GDP (OFF) and GTP (ON)-binding pan-KRAS inhibitor with Kd (GDP) = 1 nM and Kd (GTP) = 22 nM, which enables circulation-independent blockade of KRAS. AMG410 is more than 100-fold selective for KRAS than HRAS and NRAS2, binds on the same variegated pocket as KRAS G12C inhibitors, and has high potency in KRAS G12D, G12V, G12C, G13D and other mutants, IC 50 = 1-4 nM. AMG140 regresses tumors and reduces phosphorylated ERK levels in colorectal, pancreatic and lung models of KRAS mutations.

T025 is a pan CLK inhibitor with Kds of 4.8, 0.096, 6.5, 0.61, and 0.074 nM for CLK1-4, respectively. T025 displays anti-proliferative activities with IC50s of 30-300 nM in hematological and solid cancer cell lines. T025 can be used in studies about MYC-driven diseases.

AMG 511 is a potent and orally available pan inhibitor of class I PI3Ks (Kis of 4 nM, 6 nM, 2 nM, and 1 nM for PI3Kα, β, δ, and γ, respectively), exhibiting anti-tumor activity in a mouse glioblastoma xenograft model[1]. AMG 511 significantly suppresses PI3K signaling as indicated by a decrease in p-Akt (Ser473).

PF-06273340 is an effective, Selective, and Peripherally Restricted Pan-Trk inhibitor (IC50: Trk-A = 6 nM; Trk-B = 4 nM; Trk-C = 3 nM). PF-06273340 has low metabolic turnover in HLM and hHep is a good substrate for efflux transporters P-gp (ER = 35.7) and BCRP (ER = 4.0) and has moderate passive permeability (RRCK Papp = 5.4 × 10 6 cm s 1).

Pan-KRAS Ligand 1 serves as a ligand for the target protein of PROTAC (Ligand for Target Protein for PROTAC). This compound facilitates the synthesis of PROTAC Pan-KRAS Degrader 4.

Pan-KRAS degrader 4 (compound 69) is a cereblon-based PROTAC KRAS degrader exhibiting anticancer activity with a DC50 value of less than 100 nM.

FGFR-IN-15 (compound 18i) acts as a pan-FGFR inhibitor, exhibiting potent inhibitory activity against FGFR1-4.

Dactolisib (BEZ235) hydrochloride is an orally active dual inhibitor of pan-class I PI3K and mTOR, targeting p110α γ δ β and mTOR, with IC50 values of 4 nM, 5 nM, 7 nM, 75 nM, and 20.7 nM, respectively. It inhibits both mTORC1 and mTORC2.

Destruxin B2 is a cyclic hexadepsipeptide mycotoxin that has been found in M. anisopliae and has antiviral, insecticidal, and phytotoxic activities.1,2,3 It inhibits secretion of hepatitis B virus surface antigen (HBsAg) by Hep3B cells expressing hepatitis B virus (HBV) DNA (IC50 = 1.3 μM).1 Destruxin B2 is toxic to Sf9 insect cells in an electric cell-substrate impedance sensing (ECIS) test with a 50% inhibitory concentration (ECIS50) value of 92 μM.4 It is also phytotoxic to B. napus leaves.3 |1. Yeh, S.F., Pan, W., Ong, G.-T., et al. Study of structure-activity correlation in destruxins, a class of cyclodepsipeptides possessing suppressive effect on the generation of hepatitis B virus surface antigen in human hepatoma cells. Biochem. Biophys. Res. Commun. 229(1), 65-72 (1996).|2. Male, K.B., Tzeng, Y.-M., Montes, J., et al. Probing inhibitory effects of destruxins from Metarhizium anisopliae using insect cell based impedance spectroscopy: Inhibition vs chemical structure. Analyst 134(7), 1447-1452 (2009).|3. Buchwaldt, L., and Green, H. Phytotoxicity of destruxin B and its possible role in the pathogenesis of Alternaria brassicae. Plant Pathol. 41(1), 55-63 (1992).

MSA-2 dimer, a selective and orally active non-nucleotide STING agonist with a dissociation constant (Kd) of 145 μM, demonstrates prolonged antitumor and immunogenic activity. It non-covalently binds to STING as a dimer, showing greater permeability compared to cyclic dinucleotide[1].

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].

CAY17c is an inhibitor of bromodomain-containing protein 4 (BRD4; IC50= 0.71 μM), as well as class I histone deacetylases (HDACs; IC50s = 0.046, 0.058, 0.075, and 0.167 μM for HDAC1, -2, -3, and -8, respectively) and class IIb HDACs (IC50s = 0.073 and 0.923 μM for HDAC6 and HDAC10, respectively).1It is selective for these enzymes over BRD2, -3, and -T (IC50s = >20 μM for all), as well as over HDAC4, -5, -7, -9, and -11 (IC50s = >10 μM for all). CAY17c inhibits the proliferation of HCT116, SW620, and DLD-1 colorectal cancer cells (IC50s = 0.45, 1.78, and 2.11 μM, respectively), as well as induces apoptosis and autophagy in HCT116 cells. It reduces tumor growth in an HCT116 mouse xenograft model when administered at doses of 15 and 30 mg/kg. 1.Pan, Z., Li, X., Wang, Y., et al.Discovery of thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as bromodomain-containing protein 4/histone deacetylase dual inhibitors induce autophagic cell death in colorectal carcinoma cellsJ. Med. Chem.63(7)3678-3700(2020)

PI3K mTOR Inhibitor-4 is an orally active pan-I PI3K mTOR enzyme inhibitor, acting on PI3Kα (IC50: 0.63 nM), PI3Kγ (IC50: 22 nM), PI3Kδ (IC50: 9.2 nM), and mTOR (IC50: 13.85 nM). PI3K mTOR Inhibitor-4 can be used to study cancer.

AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor for Aurora A B C with IC50 values of 5 nM, 4 nM, and 1 nM, respectively. It exhibits over 10-fold selectivity for Aurora kinases compared to p38α, Tyk2, JNK2, Met, and Tie2. [Phase 1].