piperidines and palbociclib

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

Topics: Aminopyridines; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; DNA Breaks, Double-Stranded; Estrogen Receptor alpha; Female; Flavonoids; Humans; Piperazines; Piperidines; Protein Kinase Inhibitors; Purines; Pyridines

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperazines; Piperidines; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Survival Rate

The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.

Topics: 4-Butyrolactone; Amines; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinases; Drug Screening Assays, Antitumor; Female; Humans; Molecular Targeted Therapy; NF-kappa B; Ovarian Neoplasms; Piperazines; Piperidines; Prodrugs; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Sesquiterpenes; Signal Transduction; Structure-Activity Relationship

The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 h. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5' pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by 'super-enhancers'. At the 3' ends of genes, treatment with THZ1 suppressed RNA polymerase 'read through' at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in poly A sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3' effects were due to altered CDK7 activity at the 5' end of long genes, and were likely to be due to slower rates of elongation.

Topics: 3' Flanking Region; 5' Flanking Region; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cyclic N-Oxides; Cyclin-Dependent Kinase 9; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Flavonoids; Gene Expression Regulation, Leukemic; Humans; Indolizines; Myeloid Cells; Phenylenediamines; Piperazines; Piperidines; Piperidones; Protein Kinase Inhibitors; Pyridines; Pyridinium Compounds; Pyrimidines; Pyrroles; RNA Polymerase II; Translocation, Genetic

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cyclic N-Oxides; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Enhancer Elements, Genetic; Gene Expression Regulation, Neoplastic; Humans; Indolizines; Introns; Molecular Targeted Therapy; Oncogene Addiction; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyridines; Pyridinium Compounds; Quinazolines; Thyroid Gland; Thyroid Neoplasms; Tissue Array Analysis; Transcription, Genetic

Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.

Topics: Aminopyridines; Ataxia Telangiectasia Mutated Proteins; Cyclin-Dependent Kinases; Drug Design; Estradiol; Fulvestrant; Imatinib Mesylate; Piperazines; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Sulfoxides; Vardenafil Dihydrochloride

Topics: Adenine; Antineoplastic Agents; Drug Evaluation; Humans; Neoplasms; Patient Selection; Piperazines; Piperidines; Pragmatic Clinical Trials as Topic; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Design

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinases; Cysteine; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Mutation; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Serine