Search

Poly (ADP‐ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high‐throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti‐tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type‐I interferon response is triggered through the induction of the cGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi. [ABSTRACT FROM AUTHOR]

Background: The enhancement of DNA damage repair is one of the important mechanisms of platinum resistance. Protein cell division cycle 7 (CDC7) is a conserved serine/threonine kinase that plays important roles in the initiation of DNA replication and is associated with chemotherapy resistance in ovarian cancer. However, whether the CDC7 inhibitor XL413 has antitumor activity against ovarian cancer and its relationship with chemosensitivity remain poorly elucidated. Methods: We evaluated the antitumor effects of carboplatin combined with XL413 for ovarian cancer in vitro and in vivo. Cell viability inhibition, colony formation and apoptosis were assessed. The molecules related to DNA repair and damage were investigated. The antitumor effects of carboplatin combined with XL413 were also evaluated in SKOV-3 and OVCAR-3 xenografts in subcutaneous and intraperitoneal tumor models. Results: Sequential administration of XL413 after carboplatin (CBP) prevented cellular proliferation and promoted apoptosis in ovarian cancer (OC) cells. Compared with the CBP group, the expression level of RAD51 was significantly decreased and the expression level of γH2AX was significantly increased in the sequential combination treatment group. The equential combination treatment could significantly inhibit tumor growth in the subcutaneous and intraperitoneal tumor models, with the expression of RAD51 and Ki67 significantly decreased and the expression of γH2AX increased. Conclusions: Sequential administration of CDC7 inhibitor XL413 after carboplatin can enhance the chemotherapeutic effect of carboplatin on ovarian cancer cells. The mechanism may be that CDC7 inhibitor XL413 increases the accumulation of chemotherapy-induced DNA damage by inhibiting homologous recombination repair activity.

Summary: In this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0). From Cycle 1, all patients received 50 mg PIC QD on Days 1–14 followed by a 7-day rest period. Twenty patients were enrolled. Median Tmax was achieved approximately 2 h post-dose of TAK-931 80 mg for both tablet and PIC. Geometric mean Cmax, AUC exposures, and T1/2z of TAK-931 were similar for both formulations. Geometric mean Cmax, AUClast, and AUCinf ratios were 0.936 (90% confidence interval [CI]: 0.808–1.084), 1.004 (90% CI: 0.899–1.120), and 1.007 (90% CI: 0.903–1.123), respectively, for TAK-931 tablet in reference to PIC. Discontinuation of TAK-931 due to treatment-emergent adverse events (TEAEs) occurred in 1 patient. Four (20%) patients experienced a serious TEAE; none were considered related to TAK-931. Pharmacokinetics and systemic exposure profiles were similar following administration of both formulations, supporting the transition from PIC to tablet in the clinical development of TAK-931. (Trial registration numberClinicalTrials.gov NCT03708211. Registration date October 12, 2018). [ABSTRACT FROM AUTHOR]

A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood–brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS.

Background: Genomic instability is a hallmark of cancer cells, and this cellular phenomenon can emerge as a result of replicative stress. It is possible to take advantage of replicative stress, and enhance it in a targeted way to fight cancer cells. One of such strategies involves targeting the cell division cycle 7-related protein kinase (CDC7), a protein with key roles in regulation of initiation of DNA replication. CDC7 overexpression is present in different cancers, and small molecule inhibitors of the CDC7 have well-documented anti-tumor effects. Here, we aimed to test the potential of CDC7 inhibition as a new strategy for glioblastoma treatment. Methods: PHA-767491 hydrochloride was used as the CDC7 inhibitor. Two glioblastoma cell lines (U87-MG and U251-MG) and a control cell line (3T3) were used to characterize the effects of CDC7 inhibition. The effect of CDC7 inhibition on cell viability, cell proliferation, apoptosis, migration, and invasion were analyzed. In addition, real-time PCR arrays were used to identify the differentially expressed genes in response to CDC7 inhibition. Results: Our results showed that CDC7 inhibition reduces glioblastoma cell viability, suppresses cell proliferation, and triggers apoptosis in glioblastoma cell lines. In addition, we determined that CDC7 inhibition also suppresses glioblastoma cell migration and invasion. To identify molecular targets of CDC7 inhibition, we used real-time PCR arrays, which showed dysregulation of several mRNAs and miRNAs. Conclusions: Taken together, our findings suggest that CDC7 inhibition is a promising strategy for treatment of glioblastoma. [ABSTRACT FROM AUTHOR]

Abstract: A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure. [Copyright &y& Elsevier]

A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood–brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS. [ABSTRACT FROM AUTHOR]

Background: Cdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial., Methods: Here, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library., Findings: Our data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents., Interpretation: The inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy. FUND: This work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)