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This research presents an error estimation approach with the combination of traditional multilevel techniques used to minimize errors for an accurate prediction and to investigate the behavior of such an algorithm for a satellite. The traditional techniques mentioned above are a combination derived from multiple regression techniques and perform a case study for data analysis. A linear plot can easily be predicted, however if a system tends to deviate toward non-linearity the overall result derived from such an algorithm can be non-reliable since each value would depict a completely different output at different levels. The stability of the fixed regression derived is used to determine the accuracy of the system.

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356μM and AR binding IC50=

Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.

Purpose: To investigate the effects of talazoparib alone and in combination with temozolomide (TMZ) on prostate cancer cells Introduction: Talazoparib is a potent, orally bioavailable, small molecule inhibitor of PARP (poly-ADP ribose polymerase) enzyme activity that also traps PARP protein onto DNA at sites of DNA damage; both activities result in cancer cell death (Murai et al. Mol Cancer Ther. 2014;13:433-43). Talazoparib is currently under investigation for clinical activity in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations (EMBRACA; Clinical Trials.gov; NCT01945775). In the current nonclinical study, talazoparib demonstrated potent antitumor effects on androgen receptor (AR)-positive prostate cancer cells expressing both full length AR (LNCaP cells) as well as the androgen-independent splice variant, AR-V7 (22RV1 cells), when used either as a single agent or in combination with low, noncytotoxic concentrations of TMZ, a DNA alkylating therapeutic. Methods: Viability of prostate cancer cells (LNCaP and 22RV1 cells) after 7 days of treatment was measured by Cell Titer Glo (Promega) after treatment with vehicle, talazoparib, TMZ or a combination of the two. DNA damage was determined by immunofluorescence against gH2AX (EMD Millipore), and the amount of PARP trapped on DNA, determined by Western Blot analysis of chromatin probed with antibodies specific for PARP. Cellular homeostasis was determined by flow cytometry analysis for cell cycle stage, and apoptosis indicated by Annexin V staining (BD Pharmingen) or caspase activation with Caspase Glo (Promega) assays. Nucleotide adducts, N7 methyl-2'-deoxyguanosine (N7-MedG) and O6-Methyl-2'-deoxyguanosine (O6-MedG), from 1-, 2- and 4-hour TMZ-treated calf thymus DNA and genomic DNA from LNCaP cells treated with TMZ were detected after DNA hydrolysis and quantitated by LC-mass spectrometry in multiple reaction monitoring mode. Results: Talazoparib treatment resulted in a concentration-dependent inhibition of cell viability in LNCaP (AR wildtype) and 22RV1 (AR-V7) cells. Talazoparib's antitumor effects were greatly enhanced when combined with noncytotoxic TMZ concentrations. In a cell-free study using calf thymus DNA, TMZ generated both N7-MedG and O6-MedG DNA adducts, with the N7-MedG being more abundant than the O6-MedG. Analysis of DNA from LNCaP cells treated with TMZ generated detectable N7-MedG DNA adducts. Low, noncytotoxic concentrations of TMZ potentiated the effects of talazoparib on prostate cancer cell viability independent of AR variant status. Treatment with talazoparib alone and in combination with TMZ was associated with increased gH2AX staining (DNA damage) and enhanced PARP-DNA trapping complexes. The combination treatment also induced an increase in apoptotic cells at early time points. Conclusion: Talazoparib is cytotoxic to prostate cancer cells as a single agent in nonclinical cell based models. Herein, we demonstrate that combining noncytotoxic doses of TMZ with talazoparib improves efficacy in killing of LNCaP and 22RV1 cells. The increased efficacy corresponds with increased DNA-damage and increased trapped PARP-DNA complexes. Low, noncytotoxic doses of TMZ are shown to generate DNA damage sites in vitro and in treated LNCaP cells, providing a mechanistic basis for the combination effect of talazoparib and TMZ. Together, these nonclinical data provide scientific rationale for a clinical trial strategy of combining talazoparib with low, noncytotoxic doses of TMZ to enhance efficacy in prostate cancer. Citation Format: Jeffrey N. Lindquist, Vernon T. Phan, Eduardo Riquelme, Kakoli Mukherjee, Olivia Farías, Ashu Gupta, Mohd Raja, Roopa Rai, Hirdesh Uppal, Andrew A. Protter. Talazoparib efficacy is enhanced by noncytotoxic doses of temozolomide-mediated DNA damage in prostate cancer cell lines [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B30.