capan-1

Pevonedistat (MLN4924) is a potent and selective NEDD8 activating enzyme (NAE) inhibitor (IC50=4.7 nM) with therapeutic potential for myelodysplastic syndromes (MDS) and antitumor activity.

Ursolic acid (Prunol) is a natural product, a pentacyclic triterpene carboxylic acid extracted from Rhododendron caprifolium. Ursolic acid has anti-tumor, anti-inflammatory, anti-bacterial and hypoglycemic activities.

Rucaparib (PF-01367338) is a PARP protein inhibitor (PARP-1 Ki=1.4 nM) and hexose hexose-6-phosphate dehydrogenase (H6PD) inhibitor with oral activity. Rucaparib exhibits antitumor activity, with activity against desmoplasia-resistant prostate cancer (CRPC).

SHP099 (SHP099 free base) free base is an effective, selective, orally bioavailable, and efficacious SHP2 inhibitor (IC50 =0.07 μM and p-ERK modulation in cells IC50 = 0.250 μM). SHP099 shows dose-dependent pathway inhibition and antitumor activity in xenograft models.

1. Bruceine D from Brucea javanica, may have the potential to be used as a natural viricide, or a lead compound for new viricides. 2. Bruceine D inhibits the growth of three pancreatic cancer cell lines, i.e., PANC-1, SW199 and CAPAN-1; induces cytotoxicity in Capan-2 cells via the induction of cellular apoptosis involving the mitochondrial pathway.

Mahanimbine is found in the roots, leaves and stems of Murraya koenigii and is an orally active alkaloid extracted from Murraya koenigii. Bifidobacterium bifidum leaves on histopathological changes in pancreatic beta cells of streptozotocin-induced diabetic rats.

Rucaparib monocamsylate (Rucaparib Camsylate) is a PARP inhibitor (PARP1,Ki of 1.4 nM). Rucaparib Camsylate also displays binding affinity to eight other PARP domains.

PARP1-IN-27 (Compound 9B) serves as an inhibitor of both PARP1 and PARP2, exhibiting IC 50 values of 2.53 nM and 6.45 nM, respectively, in SUM149PT cells. This compound effectively suppresses the proliferation of BRCA-mutated cancer cell lines such as SUM149PT, HCC1937, and Capan-1, with respective IC 50 values of 0.62, 1.91, and 4.26 μM. Additionally, PARP1-IN-27 exacerbates DNA double-strand breaks, enhances ROS production, causes G2 M phase cell cycle arrest, and triggers apoptosis in SUM149PT cells.

Tubulin inhibitor 48 (compound 16) is an anticancer agent targeting microtubules. It exhibits IC50 values of 0.1 μM and 0.07 μM against LN-229 and Capan-1 cells, respectively.

(rac)-Talazoparib ((rac)-BMN-673) (Compound 47) is an orally active inhibitor of PARP1 2, with Ki values of 1.2 nM and 0.87 nM, respectively. It inhibits cellular PARylation at an EC50 of 2.51 nM. This compound leads to the accumulation of DNA damage and suppresses the proliferation of BRCA1 2-mutated MX-1 and Capan-1 cells, with IC50 values of 0.3 nM and 5 nM, respectively. Additionally, (rac)-Talazoparib exhibits antitumor activity in mouse models.

CAY10760 is an inhibitor of the protein-protein interaction between RAD51 recombinase and BRCA2 (EC50= 19 μM in a cell-free competitive ELISA).1It decreases homologous recombination by 54% in wild-typeBRCA2-expressing BxPC-3 pancreatic cancer cells when used at a concentration of 20 μM. CAY10760 (20 μM) decreases proliferation of BxPC-3, as well as mutantBRCA2-expressing Capan-1, cancer cells when used alone or in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib . 1.Bagnolini, G., Milano, D., Manerba, M., et al.Synthetic lethality in pancreatic cancer: Discovery of a new RAD51-BRCA2 small molecule disruptor that inhibits homologous recombination and synergizes with olaparibJ. Med. Chem.63(5)2588-2619(2020)

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).

Rucaparib Phosphate (PF-01367338 phosphate) is an inhibitor of PARP (Ki: 1.4 nM for PARP1) that is used in clinical therapy to sensitize cancer cells to chemotherapy.

SK-575 is a degradation agent targeting protein-hydrolyzed PARP1 chimera with anticancer and antitumor activity.SK-575 effectively inhibits the growth of cancer cells harboring BRCA1 2 mutations and selectively induces PARP1 degradation in cancer cells.

SC10914 is a highly potent PARP inhibitor (PARP1 IC50 = 7.87 nM) with potent anti-proliferative activity against human BRCA deficient tumor cells (MDA-MB-436, BRCA1 deficient, IC50 = 4.03 nM, Capan-1 BRCA2 deficient, IC50 = 11.66 nM) and PTEN deficient tumor cells (HGC-27,PTEN deficient, IC50 = 0.35 μM). SC10914 showed potent anti-tumor activity in BRCA1 2 mutant tumor models and better pharmacokinetics profile has the potential to be selected as the clinical candidate for the treatment of treatment of BRCA1 2 deficient cancers.

SK-575-NEG (compound 28), a methylated derivative of SK-575, results from the methylation of the piperidine-2,6-dione's amino group in SK-575, serving as a control compound. It exhibits strong binding affinity to PARP1, with an IC50 of 2.64 nM. However, SK-575-NEG proved ineffective in promoting PARP1 degradation in MDA-MB-436 and Capan-1 cells, even at concentrations as high as 1 μM [1].

PARP1-IN-14 (compound 19k) is a potent PARP1 inhibitor with an IC50 of 0.6 ± 0.1 nM, displaying antiproliferative effects on MDA-MB-436 (BRCA1 − −) and Capan-1 (BRCA2 − −) cells, with IC50 values below 0.3 nM [1].

YCH1899, an orally active PARP inhibitor, demonstrates potent inhibition of PARP1 2 with an IC50 of less than 0.001 nM. It shows marked antiproliferative efficacy against Olaparib-resistant (Capan-1 OP) and Talazoparib-resistant (Capan-1 TP) cells with IC50 values of 0.89 nM and 1.13 nM, respectively. Moreover, YCH1899 possesses favorable pharmacokinetic attributes in rats [1].

PARP1 2-IN-3 (Compound 29) is an orally effective inhibitor of PARP1 and PARP2, exhibiting IC50 values of 0.2235 nM and <0.001 nM, respectively. It inhibits the proliferation of Capan-1 wild-type, AZD2281-resistant, and BMN673-resistant cells, with IC50 values ranging from 1.82 to 9.98 nM. Furthermore, PARP1 2-IN-3 demonstrates anti-tumor activity in mice.