Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407.

INTRODUCTION: In the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment. METHODS: Eligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point. RESULTS: After median (range) follow-up of 14.3 (0.1-31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. CONCLUSIONS: Pembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.

Improving trends in survival of patients who receive chemotherapy for metastatic or recurrent gastric cancer: 12 years of experience at a single institution.

BACKGROUND: The aim of this retrospective study was to evaluate the changes in clinical features and treatment outcomes of the patients with metastatic or recurrent gastric cancer (MRGC) treated in the past 12 years. METHODS: A total of 3888 patients who received chemotherapy for MRGC between January 2000 and December 2011 were analyzed via a prospectively collected registry. The analysis focused on the comparison among three periods: 2000-2003 (period 1), 2004-2007 (period 2) and 2008-2011 (period 3). RESULTS: There were 880 patients (23%) in period 1, 1573 (40%) in period 2 and 1435 (37%) in period 3. The most commonly used first-line chemotherapy regimen was fluoropyrimidine with/without platinum (72%) for all periods. The use of second- and third-line chemotherapy was slightly but significantly more common in the two recent periods: 46 and 19 % in period 1, 54 and 26% in period 2, and 53 and 27% in period 3, respectively. Overall, 3494 patients (89.9%) died with a median overall survival (OS) of 10.6 months (95% CI 10.2-11.0). The OS was statistically significantly improved over the study period: 9.6 months (95% CI 9.0-10.2) in period 1, 10.3 months (95% CI 9.8-10.9) in period 2 and 11.7 months (95% CI 11.0-12.4) in period 3 (p for trend <0.001). Multivariate analysis including eight prognostic factors (performance, gastrectomy, peritoneal/bone/lung metastasis, abnormal alkaline phosphatase/albumin/total bilirubin) showed that the more recent treatment period was an independent favorable prognostic factor for OS (p < 0.001). CONCLUSION: The OS of patients who receive chemotherapy for MRGC has been shown to improve over time.

(S)-tetrahydroisoquinoline alkaloid inhibits LPS-induced arachidonic acid release through downregulation of cPLA2 expression.

Sepsis, a systemic inflammatory response syndrome, remains a potentially lethal condition. (S)-1-α-Naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) is noted as a drug candidate for sepsis. Many studies have demonstrated its significant anti-inflammatory effects. Here we first examined whether CKD712 inhibits lipopolysaccharide (LPS)-induced arachidonic acid (AA) release in the RAW 264.7 mouse monocyte cell line, and subsequently, its inhibitory mechanisms. CKD712 reversed LPS-associated morphological changes in the RAW 264.7 cells, and inhibited LPS-induced release of AA in a concentrationdependent manner. The inhibition was apparently due to the diminished expression of a cytosolic form of phospholipase A2 (cPLA2) by CKD712, resulting from reduced NF-κB activation. Furthermore, CKD712 inhibited the activation of ERK1/2 and SAP/JNK, but not of p38 MAPK. CKD712 had no effect on the activity or phosphorylation of cPLA2 and on calcium influx. Our results collectively suggest that CKD712 inhibits LPS-induced AA release through the inhibition of a MAPKs/NF-κB pathway leading to reduced cPLA2 expression in RAW 264.7 cells.

Three-week combination chemotherapy with S-1 and cisplatin as first-line treatment in patients with advanced gastric cancer: a retrospective study with 159 patients.

BACKGROUND: Doses and schedules of the combination of S-1 and cisplatin for the treatment of advanced gastric cancer (AGC) have not been standardized. We therefore evaluated the efficacy and feasibility of a 3-week schedule of S-1 and cisplatin in patients with AGC, as well as assessing factors prognostic of patient outcomes. METHODS: A total of 159 patients with AGC were treated with S-1 (40 mg/m(2) bid on days 1-14) and cisplatin (60 mg/m(2) IV on day 1) between January 2004 and December 2008. RESULTS: Median follow-up duration was 20.0 months (range, 11.4-48.5 months), during which time 129 patients (81.1%) died. Patients received a median 6 cycles of chemotherapy (range, 1-19 cycles). Among the 59 patients with measurable disease, 1 achieved a complete response (1.7%) and 24 (40.7%) had partial responses, giving an overall response rate of 42.4% (95% CI, 23.0-61.8%). The median progression-free survival (PFS) was 5.8 months (95% CI, 4.8-6.9 months), and the median overall survival (OS) was 11.3 months (95% CI, 9.6-13.0 months). Multivariate analysis showed that initial metastasis, bone metastasis, and liver metastasis were independent prognostic factors for reduced PFS, whereas poor performance status, initial metastasis, and bone metastasis were prognostic for reduced OS. Application of a previous prognostic model showed that observed PFS and OS survival curves for patients in various risk groups differed significantly (P < 0.001 each). CONCLUSIONS: A 3-week regimen of S-1 plus cisplatin was active and well tolerated as first-line treatment in patients with AGC. Disease status and bone metastasis were the most important prognostic factors.

CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C.

CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, was considered as a new effective drug candidate to sepsis, based on its anti-inflammatory activity. It was reported that CKD712 inhibited various signal pathways which play a key role in production of proinflammatory cytokines. Here, we examined the effect of CKD712 on the secretion of high mobility group box 1 (HMGB1), which is one of the proinflammatory cytokines. CKD712 can reduce Gram-negative lipopolysaccharide (LPS)- and Gram-positive lipoteichoic acid (LTA)-stimulated HMGB1 secretion in RAW264.7 and human peripheral blood monocytes (PBMo), and also reduce LPS-induced nucleocytoplasmic translocation of HMGB1 1h before or after LPS treatment. CKD712 could dose-dependently inhibit the activation of PI3K and PI3K-dependent kinase 1 (PDK1), which are involved in HMGB1 secretion signaling pathway. In addition, CKD712 inhibited classical protein kinase C (cPKC), the effective kinase for phosphorylation of HMGB1 for secretion, however, had no effect on histone acetyl-transferase activity, which is another mechanism known for HMGB1 secretion. Thus, we suggest that CKD712 could inhibit LPS- and LTA-stimulated HMGB1 secretion through the inhibition of HMGB1 phosphorylation by inhibiting PI3K-PKC signaling pathway.

Biochemical characterization of metnase's endonuclease activity and its role in NHEJ repair.

Metnase (SETMAR) is a SET-transposase fusion protein that promotes nonhomologous end joining (NHEJ) repair in humans. Although both SET and the transposase domains were necessary for its function in DSB repair, it is not clear what specific role Metnase plays in the NHEJ. In this study, we show that Metnase possesses a unique endonuclease activity that preferentially acts on ssDNA and ssDNA-overhang of a partial duplex DNA. Cell extracts lacking Metnase poorly supported DNA end joining, and addition of wt-Metnase to cell extracts lacking Metnase markedly stimulated DNA end joining, while a mutant (D483A) lacking endonuclease activity did not. Given that Metnase overexpression enhanced DNA end processing in vitro, our finding suggests a role for Metnase's endonuclease activity in promoting the joining of noncompatible ends.

A prognostic model in patients who receive chemotherapy for metastatic or recurrent gastric cancer: validation and comparison with previous models.

PURPOSE: To make up for the limitations of previous prognostic models, we developed and validated a model in patients with metastatic or recurrent gastric adenocarcinoma (AGC), and to compare with previous models. METHODS: A total of 2,805 patients received chemotherapy for AGC in Asan Medical Center between January 2000 and December 2008 and were randomly split into training and validation sets of 1,870 and 935 patients, respectively. A prognostic model was developed from the training set. RESULTS: The median follow-up duration was 26.5 months (range, 10.8-116.3), during which time 2,495 patients (88.9%) died. Eight factors associated with poor prognosis were identified by multivariate analysis: ECOG performance status ≥2 (2 points), no gastrectomy, peritoneal metastasis, bone metastasis (2 points), lung metastasis, alkaline phosphatase > 120 IU/l, albumin < 3.3 g/dL, and total bilirubin > 1.2 mg/dL. A prognostic model was developed by dividing patients into good (0-1 points), moderate (2-3), and poor (≥4) risk groups. The overall survival (OS) curves for three risk groups differed significantly for both the training and the validation sets (P < 0.001 each). In the training set, the median OS for the three risk groups was 14.0, 9.4, and 5.1 months, respectively. Application of three previous prognostic models to our validation set showed that the four models, including ours, had similar ability to predict survival outcomes (c-statistics, 0.5520-0.5836). CONCLUSION: Validation and comparison of prognostic models indicated that our model was as effective as the previous models to stratify the patients with AGC.

CKD-712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Inhibits the NF-κB Activation and Augments Akt Activation during TLR4 Signaling.

Since CKD-712 has been developed as an anti-inflammatory agent, we examined the effect of CKD-712 during TLR4 signaling. Using HEK293 cells expressing TLR4, CKD-712 was pre-treated 1 hr before LPS stimulation. Activation of NF-κB was assessed by promoter assay. The activation of ERK, JNK, p38, IRF3 and Akt was measured by western blotting. CKD-712 inhibited the NF-κB signaling triggered by LPS. The activation of ERK, JNK, p38 or IRF3 was not inhibited by CKD-712. On the contrary the activation of these molecules was augmented slightly. The activation of Akt with stimulation of LPS was also enhanced with CKD-712 pre-treatment at lower concentration, but was inhibited at higher concentration. We suggest that during TLR4 signaling CKD-712 inhibits NF-κB activation. However, CKD-712 augmented the activation of Akt as well as Map kinases. Therefore, we suggest that CKD-712 might have a role as an immunomodulator.

Discovery of a potent tubulin polymerization inhibitor: synthesis and evaluation of water-soluble prodrugs of benzophenone analog.

Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3·HCl (l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3·HCl intravenously, with rapid clearance of 3·HCl indicating the effective cleavage of prodrug. Compound 3·HCl (CKD-516) has now been progressed to phase 1 clinical trial.

Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors.

Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

Single-dose mitoxantrone in combination with continuous infusion intermediate-dose cytarabine plus etoposide for treatment of refractory or early relapsed acute myeloid leukemia.

This prospective phase II clinical trial evaluated the effects of single-dose mitoxantrone (36 mg/m2 on day 1) in combination with continuous infusion intermediate-dose cytarabine plus etoposide in 25 patients with refractory or early relapsed acute myeloid leukemia (AML). We compared the results of our current study with those of a previous phase II trial, which had the same eligibility criteria and chemotherapy schedule except that a conventional divided dose of mitoxantrone (12 mg/m2 on days 1-3) was used. The complete remission (CR) rate was significantly lower with the single-dose mitoxantrone regimen than with the divided-dose regimen (24.0% vs. 51.5%; P=0.034), mainly owing to an increased incidence of hypoplastic deaths. CR duration and overall survival were not significantly different between the two regimens. In conclusion, single-dose mitoxantrone was inferior to conventional divided-dose mitoxantrone for treatment of refractory or early relapsed AML in terms of CR rate.

Synthesis of novel diaryl ethers and their evaluation as antimitotic agents.

A series of novel diaryl ethers possessing various functional groups were synthesized and evaluated for antiproliferative activity in human myeloid leukemia HL-60 cells. Among the compounds examined, compounds 10, 17, 20, 24, and 33 showed moderate to potent antiproliferative activity. These derivatives were further examined in terms of their abilities to inhibit tubulin polymerization; however, all of the tested compounds were relatively ineffective. The reference compound E7010 with an IC(50) of 0.34 microM exhibited potent antiproliferative activity and significantly inhibited tubulin polymerization in a dose-dependent manner.

Novel alpha-glucosidase inhibitors, CKD-711 and CKD-711a produced by Streptomyces sp. CK-4416. III. Physico-chemical properties and structure elucidation.

We have isolated two novel a-glucosidase inhibitors, O-[4-deoxy-4-(2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl-amino)-alpha-D-glucopyranosyl]-(1-->4)-O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranose (named CKD-711) and its hexameric analog CKD-711a, from the fermentation broth of Streptomyces sp. CK-4416. HRFAB-MS and NMR analyses reveal that molecular formulae of CKD-711 and CKD-711a are C25H43NO20 and C37H63NO30, respectively with the latter containing two more glucose moieties than the former. Detailed chemical structures of both compounds have been characterized by high-resolution two-dimensional NMR methods.