paca

Epacadostat (INCB 024360) is an oral-available inhibitor of indoleamine 2, 3-dioxygenase (IDO1), increasing the proliferation and activation of various immune cells and reducing tumor-associated regulatory T cells.

PACAP 1-38 acetate is a pituitary adenylate cyclase activating polypeptide (PACAP) analogue. PACAP 1-38 acetate binds to PACAP type I receptor(IC50 = 4 nM) and PACAP type II VIP2 receptor(IC50 = 1 nM) but not to PACAP type II, VIP1 receptor.

PACAP (6-38), human, ovine, rat acetate is a potent PACAP receptor antagonist with IC50s of 30, 600, and 40 nM for PACAP type I receptor, PACAP type II receptor VIP1, and PACAP type II receptor VIP2, respectively.

PACAP-38 (31-38), human, mouse, rat acetate is an activator of PAC1 receptor. PACAP-38 (31-38), human, mouse, rat acetate demonstrates potent, efficacious, and sustained stimulatory effects on sympathetic neuronal NPY and catecholamine production and can

PACAP (1-27), human, ovine, rat acetate (PACAP 1-27 acetate) is a novel neuropeptides originally isolated from bovine hypothalamus, also found in humans and rats.

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.

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.

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.

Pituitary adenylate cyclase-activating peptide (PACAP) (6-27) is a PACAP receptor antagonist with IC50 values of 1,500, 600, and 300 nM, respectively, for rat PAC1, rat VPAC1, and human VPAC2 recombinant receptors expressed in CHO cells. It binds to PACAP receptors on SH-SY5Y and SK-N-MC human neuroblastoma and T47D human breast cancer cells (IC50s = 24.5, 106, and 105 nM, respectively) and inhibits cAMP accumulation induced by PACAP (1-38) (Kis = 457, 102, and 283 nM, respectively, in SH-SY5Y, SK-N-MC, and T47D cells). In vivo, in newborn pigs, PACAP (6-27) (10 μM) inhibits vasodilation of pial arterioles induced by PACAP (1-27) and PACAP (1-38) . It also inhibits PACAP (1-27)-stimulated increases in plasma insulin and glucagon levels and pancreatic venous blood flow in dogs when administered locally to the pancreas at a dose of 500 μg.

PACAP (1-27), human, ovine, rat TFA (PACAP 1-27 TFA), an N-terminal fragment of PACAP-38, is an effective PACAP receptor antagonist with IC50 values of 3 nM for rat PAC1, 2 nM for rat VPAC1, and 5 nM for human VPAC2.

PACAP (6-27) (human, ovine, rat) is an antagonist for the PACAP receptor, inhibiting the catecholamine response of the canine adrenal gland to vasoactive intestinal peptide (VIP), making it a valuable compound for research into cardiovascular and neurological disorders [1].

PACAP-related peptide (PRP) is an endogenous 29-amino acid peptide that belongs to the secretin/glucagon superfamily of peptides, which includes secretin , glucagon , glucagon-like peptide-1 , GLP-2 , and pituitary adenylate cyclase-activating polypeptide . It is expressed in normal human pancreas and adrenal gland tissue and in some tumors that produce vasoactive intestinal peptide (VIP). PRP (1-29) is secreted by CHO-K1 cells that express human recombinant preproPACAP.

PACAP (1-38), human, ovine, rat (Pituitary Adenylate Cyclase Activating Polypeptide 38), is a neuropeptide comprising 38 amino acid residues.

PACAP (1-38), a novel neuropeptide isolated from the bovine hypothalamus is more active than vasoactive intestinal peptide (VIP) in stimulating adenylate cyclase (EC50=7 nM). PACAP 1-38 (10-9 M) increased substance P (SP), gastrin releasing peptide (GRP),

PACAP-38 (16-38), human, mouse, rat, exhibits potent, efficacious, and sustained stimulatory effects on sympathetic neuronal NPY and catecholamine production.

PACAP-related peptide (PRP) is an endogenous 29-amino acid peptide that belongs to the secretin/glucagon superfamily of peptides, which includes secretin , glucagon , glucagon-like peptide-1 , GLP-2 , and pituitary adenylate cyclase-activating polypeptide . It is expressed in rat hypothalamus as well as within the nerves of the median eminence, the anterior pituitary, bed nucleus of the stria terminalis, cerebellum, cerebral cortex, and amygdala. PRP is also expressed in vaginal, uterine cervical, uterine horn, fallopian tube, and ovarian tissues from the rat female genital tract and is present in extracts of male testis tissue.

PACAP (1-38) free acid TFA, an endogenous neuropeptide, effectively enhances antral motility and somatostatin secretion, while concurrently suppressing gastrin secretion and promoting the release of vasoactive intestinal polypeptide, gastrin-releasing peptide, and substance P. Additionally, it amplifies N-methyl-D-aspartate receptor function and brain-derived neurotrophic factor expression via RACK1 [1] [2].

PACAP (1-38) free acid, an endogenous neuropeptide, potently modulates gastrointestinal and neuroendocrine functions. It enhances antral motility, increases somatostatin secretion, and stimulates the release of vasoactive intestinal polypeptide, gastrin releasing peptide, and substance P, while concurrently inhibiting gastrin secretion. Additionally, it augments N-methyl-D-aspartate receptor function and upregulates brain-derived neurotrophic factor expression via RACK1 [1] [2].

PACAP-38 (31-38), human, mouse, rat (TFA), exhibits potent, efficacious, and sustained stimulatory effects on sympathetic neurons.

[Arg-15,-20,-21, Leu17]-PACAP-Gly-Lys-Arg-NH2 (BM-PACAP) is a synthetic analogue of PACAP 1-27 that exhibits a relaxant effect [1].

Pacanalotamab (AMG 420; BI-836909) is a bispecific T-cell engager (BiTE) that specifically targets BCMA (B cell maturation antigen) and CD3ɛ. By redirecting T cells to cells expressing BCMA, Pacanalotamab facilitates the T-cell mediated lysis of human multiple myeloma (MM) cell lines [1].

PACAP (6-38), human, ovine, rat TFA is a potent PACAP receptor antagonist with IC50 values of 30 nM, 600 nM, and 40 nM for the PACAP type I receptor, PACAP type II receptor VIP1, and PACAP type II receptor VIP2, respectively.

PACAP-38 (31-38), [human, mouse, rat], exhibits potent, efficacious, and sustained stimulatory effects on sympathetic neuronal NPY and catecholamine production.

PACAP-Related Peptide (PRP), human, a 29-amino acid region of the PACAP precursor protein, is synthesized in sufficient quantities for biological and structural studies.

Impacarzine is a biochemical.

PACAP (6-38), human, ovine, rat, is a potent and selective antagonist of PACAP 38, outperforming PACAP (6-27) in inhibiting PACAP-27-stimulated pituitary adenylate cyclase.

PACAP (1-27) (the N-terminal fragment of PACAP-38) is a novel neuropeptides originally isolated from bovine hypothalamus, also found in humans and rats.

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.

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].

MET PDGFRA-IN-1 (compound 8c) is an inhibitor of MET and PDGFRA proteins, with an IC50 of 36 μM against MET. It inhibits MET phosphorylation, induces apoptosis, and reduces proliferation in various MET-positive cell lines, showing 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].

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].

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)

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

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

KRAS inhibitor-17 (compound 3-9) is a potent inhibitor of KRAS G12C with an IC50 of 3.37 μM. It exhibits p-ERK inhibition with an IC50 of 9.25 μM in MIA PaCA-2 cells and greater than 33.3 μM in A549 cells. KRAS inhibitor-17 has potential applications in the study of 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.

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).

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

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).

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

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.

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

MET PDGFRA-IN-2 (compound 8h) is an inhibitor of MET and PDGFRA proteins that promotes apoptosis and impedes 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) and exhibited p-ERK inhibition in MIA PaCA-2 and A549 cells with IC50s of 66.4 μM and 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.