LXH254 is a potent C-Raf and B-Raf inhibitor.

Adagrasib (MRTX849) is an orally active and selective covalent inhibitor of KRAS G12C. Adagrasib binds to the GDP state of the inactive conformation of KRAS G12C and inhibits KRAS and its downstream signaling. Adagrasib exhibits inhibitory activity against KRAS G12C mutant tumors.

BN82002 (CDC25 Phosphatase Inhibitor I) is a synthetic inhibitor of CDC25 phophatases

Royleanone possesses cytotoxic activity against the human pancreatic cancer cell line MIA PaCa-2.

MM41 is a human telomeric and gene promoter DNA quadruplex stabilizer with an IC50 of <10 nM against the MIA PaCa-2 pancreatic cancer cell line.

YN14 is a highly potent and selective KRASG12C proteolysis targeting chimera (PROTAC) capable of forming a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). It exhibits antiproliferative effects, significantly inhibiting the growth of KRASG12C-mutant cancer cells, and demonstrates tumor regression with tumor growth inhibition (TGI%) rates exceeding 100% in the MIA PaCa-2 xenograft model.

1-Alaninechalmydocin is a fungal metabolite originally isolated from a Great Lakes-derived Tolypocladium sp. and an inhibitor of histone deacetylases (HDACs). It reduces total HDAC activity in HeLa cell lysates in a concentration-dependent manner. 1-Alaninechlamydocin reduces proliferation of MIA PaCa-2, PANC-1, and hTERT-HPNE cells (GI50s = 5.3, 14, and 2.0 nM, respectively).

Akt1-IN-1 is a potent and selective inhibitor of Akt1, demonstrating an IC50 of 18.79 nM in MIA PaCa-2 cells, indicating its high efficacy in inhibiting this specific kinase. Notably, it shows no significant teratogenicity, hepatotoxicity, or cardiotoxicity (No Observed Adverse Effect Level > 100 µM), making it a viable candidate for anticancer research.

MASTL-IN-2 is a potent inhibitor of microtubule-associated serine/threonine kinase-like (MASTL). It demonstrates notable efficacy in suppressing the proliferation of human epithelial MIA PaCa cancer cells, exhibiting an IC50 value of 2.8 nM [1].

SB-1295, an orally active CDK9/T1 inhibitor with an IC50 of 0.17 μM, exhibits antiproliferative effects on HCT 116 and MIA PaCa-2 cells. It promotes cell death in MIA PaCa-2 by elevating intracellular ROS levels, diminishing mitochondrial membrane potential, and triggering apoptosis. This compound holds potential for cancer research [1].

MET/PDGFRA-IN-1 (compound 8c) serves as an inhibitor of MET and PDGFRA proteins, displaying an IC50 of 36 μM against MET. It impedes MET phosphorylation, thereby promoting apoptosis, and curtails the proliferation of various MET-positive cell lines, with IC50 values of 15.3 μM for AsPc-1, 19.0 μM for EBC-1, 22.0 μM for MKN-45, 25.6 μM for Mia-Paca-2, 21.0 μM for HT-29, and 31.5 μM for K562 [1].

SHP2-IN-22, a potent SHP2 allosteric inhibitor, exhibits an IC50 value of 17.7 nM and effectively suppresses proliferation, migration, and invasion in MIA PaCa-2 pancreatic cancer cells. This compound is utilized in the study of Kirsten rat sarcoma viral oncogene (KRAS) mutant cancer research [1].

KRAS inhibitor-14 is a potent inhibitor of KRAS G12C (IC50: 0.249 μM). KRAS inhibitor-14 exhibited p-ERK inhibition in MIA PaCA-2, A549 cells with IC50s of 1.12, >33.3 μM, respectively. KRAS inhibitor-14 has potential to be investigated in pancreatic, colorectal and lung cancers.

Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013). Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3 References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013).

QD-394 is an inducer of reactive oxygen species (ROS) production.1It induces lipid peroxidation, increases in intracellular accumulation of reactive oxygen species (ROS), and decreases in the reduced glutathione (GSH) to oxidized GSH (GSSG) ratio in MIA PaCa-2 pancreatic cancer cells when used at concentrations ranging from 0.5 to 10 μM. QD-394 is cytotoxic to MIA PaCa-2, PANC-1, and BxPC-3 cancer cells (IC50s = 0.64, 0.34, and 0.9 μM, respectively). QD-394 acts synergistically with napabucasin to reduce colony formation in MIA PaCa-2 cells. 1.Hu, S., Sechi, M., Singh, P.K., et al.A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen speciesJ. Med. Chem.63(17)9838-9855(2020)

OXPHOS-IN-1 (compound 2) is an inhibitor of oxidative phosphorylation (OXPHOS) and inhibits the growth of MIA PaCa-2 cells (IC50: 2.34 μM) and BxPC-3 cells (IC50: 13.82 μM).

KRAS inhibitor-12 (compound 6-1) is a potent inhibitor of KRAS G12C (IC50: 0.537 μM). KRAS inhibitor-12 exhibits p-ERK inhibition in MIA PaCA-2, A549 cells with IC50 values of 1.3, 3.7 μM respectively. KRAS inhibitor-12 has potential to be studied in pancreatic, colorectal and lung cancers.

KRAS inhibitor-17 (compound 3-9) is a potent inhibitor of KRAS G12C (IC50: 3.37 μM). KRAS inhibitor-17 exhibits p-ERK inhibition with IC50 = 9.25 μM in MIA PaCA-2 cells and >33.3 μM in A549 cells. KRAS inhibitor-17 has the potential to be studied in pancreatic, colorectal and lung cancers.

KRAS G12C inhibitor 44 is a potent, orally active KRAS G12C inhibitor. KRAS G12C inhibitor 44 exhibits anti-proliferative effects in MIA PaCA-2 (IC50: 0.016 μM), H358 cells (IC50: 0.028 μM). inhibitor 44 has anti-tumour activity in vivo.

KRAS G12C inhibitor 61 (Example 3) demonstrates potent activity by inhibiting phospho-ERK 1/2 in MIA PaCa-2 cells, reflected in an IC50 value of 9 nM. This inhibitor is applicable in the research of pancreatic, colorectal, and lung cancers [1].

KRAS inhibitor-13 (compound 5-6) is a potent inhibitor of KRAS G12C (IC50: 0.883 μM). KRAS inhibitor-13 has a p-ERK inhibitory effect in MIA PaCA-2, A549 cells with IC50 values of 5.9 and >100 μM respectively. KRAS inhibitor-13 has potential to be studied in pancreatic, colorectal and lung cancers.

KRAS inhibitor-15 (compound 3-19) is a potent inhibitor of KRAS G12C (IC50: 0.954 μM). KRAS inhibitor-15 exhibits p-ERK inhibition in MIA PaCA-2, A549 cells with IC50s of 2.03, >33.3 μM, respectively. KRAS inhibitor-15 has potential to be studied in pancreatic, colorectal and lung cancers.

CX-5461 dihydrochloride is a potent, orally active inhibitor of Pol I-mediated rRNA synthesis that acts on HCT-116 cells (IC50: 142 nM), A375 cells (IC50: 113 nM) and MIA PaCa-2 cells (IC50: 54 nM), and to a lesser extent on Pol II (IC50 ≥ 25 μM).

MET/PDGFRA-IN-2 (compound 8h) serves as an inhibitor of MET and PDGFRA proteins, promoting apoptosis in cells and impeding the proliferation of MET-positive cells with IC50 values of 9.7, 6.1, 12.0, 11.5, 8.6, and 34.4 μM for AsPc-1, EBC-1, MKN-45, Mia-Paca-2, HT-29, and K562 cells, respectively [1].

KRAS inhibitor-18 (compound 3-10) is a potent inhibitor of KRAS G12C (IC50: 4.74 μM). KRAS inhibitor-18 exhibited p-ERK inhibition in MIA PaCA-2, A549 cells with IC50s of 66.4, 11.1 μM respectively. KRAS inhibitor-18 has potential for pancreatic, colorectal and lung cancer studies.

Transketolase-IN-4 is a transketolase inhibitor with an IC50 value of 3.9 μM.Transketolase-IN-4 inhibited Mycobacterium tuberculosis DXS with an IC50 value of 114.1 μM. Transketolase-IN-4 inhibited the SW620, LS174T, and MIA PaCa-2 tumor cell proliferation.

KRAS inhibitor-16 (compound 3-11) is a potent inhibitor of KRAS G12C (IC50: 0.457 μM). KRAS inhibitor-16 exhibits p-ERK inhibition in MIA PaCA-2, A549 cells with IC50s of 3.06, 11.1 μM respectively. KRAS inhibitor-16 has potential to be studied in pancreatic, colorectal and lung cancers.

DX3-213B is a potent, orally active inhibitor of oxidative phosphorylation (OXPHOS) complex I with an IC50 of 3.6 nM. DX3-213B blocks ATP production (IC50: 11 nM) and inhibits the growth of MIA PaCa-2 cells (GI50: 11 nM). DX3-213B can be used to study pancreatic cancer.

Gemcitabine hydrochloride (LY 188011 hydrochloride) is a synthetic cytosine nucleoside derivative and an inhibitor of DNA synthesis. Gemcitabine has antitumor and antimetabolic activities. Gemcitabine induces autophagy and apoptosis.

KRAS G12C inhibitor 47 is a potent inhibitor of KRAS G12C (IC50: 0.172 μM). KRAS G12C inhibitor 47 exhibits p-ERK inhibition in MIA PaCA-2 cells, A549 cells with IC50 values of 0.046 μM and 69.8 μM respectively. KRAS G12C inhibitor 47 showed investigational potential against pancreatic, colorectal and lung cancers.

Malformin A is a cyclopentapeptide fungal metabolite that has been found in A. niger and has diverse biological activities. It is a plant growth regulator that induces malformations in plant structure. Malformin A inhibits replication of tobacco mosaic virus (TMV) in local lesion and leaf-disc assays (IC50s = 19.7 and 45.4 μg/ml, respectively). It is cytotoxic to NCI-H460, MIA PaCa-2, MCF-7, SF-268, and WI-38 cancer cells (IC50s = 70, 50, 100, 70, and 100 nM, respectively), inhibits proliferation of PC3 and LNCaP cells (IC50s = 130 and 90 nM, respectively), and induces apoptosis and necrosis in PC3 and LNCaP cells. Malformin A also increases the accumulation of reactive oxygen species, decreases the mitochondrial membrane potential, and induces autophagy in PC3 and LNCaP cells. It is toxic to mice when administered intraperitoneally (LD50 = 3.1 mg/kg) but not orally up to doses of 50 mg/kg.

TW9 is a dual inhibitor of bromodomain 2 (BD2) in bromodomain-containing protein 4 (BRD4) and histone deacetylase 1 (HDAC1; IC50s = 0.074 and 0.29 μM, respectively).1It is selective for BD2 over BD1 in BRD4 (IC50= 0.72 μM) and for HDAC1 over HDAC2 (IC50= 2.5 μM). TW9 (50 nM) induces apoptosis in, and inhibits proliferation of, MIA PaCa-2 pancreatic cancer cells. It induces cell cycle arrest at the G1phase in HPAC pancreatic cancer cells when used at a concentration of 2 μM. TW9 acts synergistically with gemcitabine to reduce the viability of HPAC cells. 1.Zhang, X., Zegar, T., Weiser, T., et al.Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinomaInt. J. Cancer147(10)2847-2861(2020)

GW284543 (UNC10225170) is a selective inhibitor of MEK5 .