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Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

The evaluation of antioxidant compounds that counteract the mutagenic effects caused by the direct action of reactive oxygen species on DNA molecule is of considerable interest. Therefore, a series of 2,3-substituted quinazolinone derivatives (Q1-Q8) were investigated by different assays, and the relationship between their biological properties and chemical structure was examined. Genotoxicity and the potential DNA-protective effects of Q1-Q8 were evaluated by comet assay and DNA topology assay. Antioxidant activity was examined by DPPH-radical-scavenging, reducing-power, and total antioxidant status (TAS) assays. The cytotoxic effect of compounds was assessed in human renal epithelial cells (TH-1) and renal carcinoma cells (Caki-1) by MTT assay. Analysis of the structure-activity relationship disclosed significant differences in the activity depending on the substitution pattern. Derivatives Q5-Q8, bearing electron-donating moieties, were the most potent members of this series. Compounds were not genotoxic and considerably decreased the levels of DNA lesions induced by oxidants (H 2 O 2 , Fe 2+ ions). Furthermore, compounds exhibited higher cytotoxicity in Caki-1 compared to that in TH-1 cells. Substantial antioxidant effect and DNA-protectivity along with the absence of genotoxicity suggested that the studied quinazolinones might represent potential model structures for the development of pharmacologically active agents.

Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted., Competing Interests: Conflict-of-interest disclosure: D.M.B. discloses the following: AbbVie: consultant, scientific advisory board, site principal investigator (PI) of a clinical trial (grant paid to institution); ArQule: scientific advisory board, site PI of a clinical trial (grant paid to institution); Ascentage Pharma: site PI of a clinical trial (grant paid to institution); AstraZeneca: consultant, site PI of a clinical trial (grant paid to institution); BeiGene: site PI of a clinical trial (grant paid to institution); DTRM Biopharma: site PI of a clinical trial (grant paid to institution); Genentech: consultant, scientific advisory board, site PI of a clinical trial (grant paid to institution); Juno/Celgene/Bristol-Myers Squibb: site PI of a clinical trial (grant paid to institution); MEI Pharma: site PI of a clinical trial (grant paid to institution); Pharmacyclics: consultant, site PI of a clinical trial (grant paid to institution); Pfizer: consultant, scientific advisory board; Teva: consultant; TG Therapeutics: scientific advisory board, site PI of a clinical trial (grant paid to institution); Tolero Pharmaceuticals: site PI of a clinical trial (grant paid to institution); and Verastem Oncology: consultant, scientific advisory board, site PI of a clinical trial (grant paid to institution). Other guidelines/registry memberships (when sponsored or consultant also included under sponsor above): National Comprehensive Cancer Network panel member, informCLL Registry steering committee (AbbVie), Observational Trial of Real-World Treatment Utilization and Effectiveness of PI3K-inhibitors in CLL/SLL and FL (REAL) registry steering committee (Verastem Oncology), and a biosimilars outcomes research panel (Pfizer). A.H. declares no competing financial interests., (© 2020 by The American Society of Hematology.)

Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6'a, 6'b, 6'h, 6'i and 6'j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25-0.5 µg/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6'a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6'a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Mdivi-1, a selective Drp-1 inhibitor, impedes mitochondrial dynamics and suppresses cancer proliferation and progression. Cholangiocarcinoma (CCA) is a very aggressive malignancy which is refractory to chemotherapy. The study investigated the mechanism of the chemosensitizing effect of mdivi-1 in cholangiocarcinoma., Main Methods: CCA cells and HEK293 T cells were employed in the study. Cell viability and induction of apoptotic cell death were determined by the MTT and acridine orange-ethidium bromide methods. Cellular glutathione content and reactive oxygen species (ROS) formation were assessed using thiol green and 2',7'-dichlorofluorescin diacetate fluorescent probes, respectively. Mitochondrial transmembrane potential and autophagy were detected by JC-1 dye and autophagy assay. Cell cycle progression was analyzed by flow cytometry. Cell migration was measured using the wound healing assay. Proteins involved in cell proliferation and cell cycle were analyzed by western immunoblotting., Key Findings: Mdivi-1 enhanced cisplatin-induced cytotoxicity in CCA cells but not in HEK293 T cells. Mdivi-1 enhanced cisplatin induced glutathione redox stress, ROS formation, and loss of mitochondrial transmembrane potential. Moreover, mdivi-1 also inhibited autophagic flux and suppressed CCA cell migration., Significance: Mdivi-1 sensitized CCA cells to cytotoxicity of cisplatin in association with increases of oxidative stress and autophagosomes, and induced cell death via the mitochondrial pathway. Disruption of mitochondrial dynamics may be a novel strategy to improve the efficacy of chemotherapy to treat CCA., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The current study investigated the cytotoxic effect of 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (A) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (B) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis was assessed to evaluate the possible pathways induced by compound A and B. MTT assay results using A and B showed significant inhibition of MCF-7 cell viability, with IC50 values of 3. 27 ± 0.171 and 4.36 ± 0.219 μg/mL, respectively, after a 72 hour treatment period. Compound A and B did not demonstrate significant cytotoxic effects towards MDA-MB-231, WRL-68 and MCF-10A cells. Acute toxicity tests also revealed an absence of toxic effects on mice. Fluorescent microscopic studies confirmed distinct morphological changes (membrane blebbing and chromosome condensation) corresponding to typical apoptotic features in treated MCF-7 cells. Using Cellomics High Content Screening (HCS), we found that compound A and B could trigger the release of cytochrome c from mitochondria to the cytosol. The release of cytochrome c activated the expression of caspases-9 and then stimulated downstream executioner caspase-3/7. In addition, caspase-8 showed remarkable activity, followed by inhibition of NF-κB activation in A-and B-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways.

Quinazolinones represent a class of sedative and anticancer drugs. Quinazolinones-based compounds have ability to suppress prostate tumor growth via apoptosis. Apoptosis is very common in embryos and adults of normal and injured mammalian testes. Effects a new derivative of quinazolinone (4(3H) quinazolinone-2-ethyl-2-phenyl ethyl (QEPE)), on the testis of Balb/C mice embryos were investigated. QEPE was able to reduce number of germ cells and diameter of seminiferous tubules. TUNEL assay analysis indicated that reduction correlated with an increase in the number of apoptotic cell. Furthermore, electron microscope observations confirmed typical apoptotic morphologies characterized by chromatin fragmentation. Finally, RT-PCR analysis showed QEPE increases the levels of Fas/Fasl and decreases C-Flip mRNAs in the testis of exposed embryos.

Heterocyclic compounds such as quinazolinones have variety of biological and pharmacological properties (anticancer, antiinflammatory, antimicrobial, antimalaria, etc.). Effects of two new quinazolinones viz., 4(3H)-quinazolinone-2-propyl-2-phenylethyl (QPPE) and 4(3H)quinazolinone-2-ethyl-2-phenylethyl (QEPE) were investigated on Balb/C mice embryos livers-the major organ of metabolism and detoxification of drugs and toxins. Histological and pathological studies demonstrated QPPE and QEPE as producers of toxic metabolites after biotransformation, creating necrosis, fatty changes, increase in the number of band cells, hepatocytes' diameters and alkaline phosphatase, in addition to sinusoid dilation, hemorrhages and hyperemia. Transmission electron micrographs showed lipid droplets in hepatocytes' cytoplasm, necrosis, vacuolization, cytoplasm disintegration, disfigured and swollen mitochondria, irregular and abnormal nuclei, nuclei with heterochromatin, condensed chromatins, myelin figures and autophages in injured hepatocytes. In conclusion, QPPE and QEPE make toxic components after biotransformation injuring membranes and creating inflammatory reactions. They also disturb metabolism of lipids pathways and cause the appearances of lipid droplets in hepatocytes.

An environment friendly method for the synthesis of 2-oxo/thioxooctahydroquinazolin-5-one derivatives has been devised using Ceric ammonium nitrate (CAN) as catalyst and polyethylene glycol (PEG) as solvent. The cytotoxic effect of these compounds was studied on U87 human glioma cells, compounds 4c, 4d and 4e are found to exhibit excellent activity at a concentration as low as 0.06 µg/ml.

A new series of the title compounds incorporated into diverse N and O heterocyclic moieties of pharmacoavailability as anti-inflammatory and analgesic agents, were synthesized starting with 6,8-dibromo-2-phenyl-4H-3,1-benzoxazin-4-one (I) by its fusion with p-aminoacetophenone to give the new intermediate compound, 6,8-dibromo-2-phenyl-3-(4-acetylphenyl)-4(3H)-quinazolinone (II). The one pot reaction of II with the appropriate aromatic aldehydes and anhyd. ammonium acetate in the presence of either ethyl cyanoacetate or malononitrile afforded the corresponding 2(1H)-pyridones III or 2(1H)-iminopyridines IV, respectively, while its reaction with malononitrile and aromatic aldehydes in piperidine gave 2-aminopyrans V. Also, reaction of the acetyl derivative II with aromatic aldehydes afforded the corresponding 1,3-propen-1-one derivatives VI which underwent cyclization with hydrazine to give the corresponding pyrazolines VII and with urea and/or thiourea to give the corresponding tetrahydropyrimidin-2-ones and/or tetrahydropyrimidin-2-thiones VIII. Some representative examples of the new compounds showed promising anti-inflammatory and analgesic activities in experimental animals.

A series of novel 3-cyclohexyl-2-substituted hydrazino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 3-cyclohexyl-2-hydrazino quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material, 3-cyclohexyl-2-hydrazino quinazolin-4(3H)-one, was synthesized from cyclohexyl amine. Title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic behavior. The compound 3-cyclohexyl-2-(1-methylbutylidene-hydrazino)-3H-quinazolin-4-one (4c) emerged as the most active compound of the series and is moderately more potent in its analgesic and anti-inflammatory activities compared to the reference standard diclofenac sodium. Interestingly, test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid.