Highly potent dipeptidyl peptidase 8/9 (DPP8/9) inhibitors designed via relative binding free energy calculations.

Dipeptidyl peptidases (DPP) 8 and 9 are emerging enzymatic drug targets with suggested applications in acute myeloid leukaemia and HIV infection, among others. In this work, we optimised a well-known reference DPP8/9 inhibitor named 1G244, using relative binding free energy calculations. An initial retrospective, computational analysis of experimental structure-activity data of 1G244 and close structural analogues, guided the subsequent prospective design of novel inhibitors derived from the reference scaffold.

Fine-tuning of a CRISPRi screen in the seventh pandemic Vibrio cholerae.

Background: Vibrio cholerae O1 El Tor, the etiological agent responsible for the last cholera pandemic, has become a well-established model organism for which some genetic tools are available. While CRISPRi technology has been applied to V. cholerae, improvements were necessary to upscale it and enable pooled screening by high-throughput sequencing in this bacterium.

Cosolvent Molecular Dynamics Applied to DPP4, DPP8 and DPP9: Reproduction of Important Binding Features and Use in Inhibitor Design.

We present our efforts in computational drug design against dipeptidyl peptidase 4 (DPP4), DPP8 and DPP9. We applied cosolvent molecular dynamics (MD) simulations to these three protein targets of interest. Our primary motivation is the growing interest in DPP8 and DPP9 as emerging drug targets.

Targeted opening of the blood-brain barrier using VCAM-1 functionalised microbubbles and "whole brain" ultrasound.

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically.

Lamin B1 curtails early human papillomavirus infection by safeguarding nuclear compartmentalization and autophagic capacity.

Human papillomavirus (HPV) infection is a primary cause of cervical and head-and-neck cancers. The HPV genome enters the nucleus during mitosis when the nuclear envelope disassembles. Given that lamins maintain nuclear integrity during interphase, we asked to what extent their loss would affect early HPV infection.

Microbubbles Containing Lysolipid Enhance Ultrasound-Mediated Blood-Brain Barrier Breakdown In Vivo.

Ultrasound and microbubbles (MBs) offer a noninvasive method of temporarily enhancing blood-brain barrier (BBB) permeability to therapeutics. To reduce off-target effects, it is desirable to minimize the ultrasound pressures required. It has been shown that a new formulation of MBs containing lysolipids (Lyso-MBs) can increase the cellular uptake of a model drug in vitro.

Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.

Unlabelled: Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, Tb, At, Pb, Bi and Ac; β-emitting radionuclides, Y, Tb and Lu; and Auger electron (AE)-emitters Ga, Zr, In and I, for targeted radionuclide therapy (TRT).

A phase 1 'window-of-opportunity' trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

Background: Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy.

New ways to image and target tumour hypoxia and its molecular responses.

Tumour hypoxia and its molecular responses have been shown to be associated with poor prognosis. Detection of hypoxia, preferably in a non-invasive manner, could therefore predict treatment outcome and serve as a tool to individualize treatment. This review gives an overview of recent literature on hypoxia imaging markers currently used in clinical trials.

Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake.

Purpose: We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV).

Experimental Design: FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation.

TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging.

Purpose: Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models.

[(18)F]VM4-037 MicroPET Imaging and Biodistribution of Two In Vivo CAIX-Expressing Tumor Models.

Purpose: [(18)F]VM4-037 was recently developed as a positron emission tomography (PET) tracer for the detection of carbonic anhydrase IX (CAIX), a tumor-specific protein upregulated under hypoxic conditions. In this study, the accumulation of [(18)F]VM4-037 was determined in two CAIX-expressing preclinical human tumor models.

Procedures: U373 and HT29 tumor-bearing animals were injected with [(18)F]VM4-037 and underwent microPET imaging up to 4 h post-injection (p.

A comparative study of the hypoxia PET tracers [¹⁸F]HX4, [¹⁸F]FAZA, and [¹⁸F]FMISO in a preclinical tumor model.

Purpose: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [(18)F]FMISO, [(18)F]FAZA, and [(18)F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification.

Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: a new concept of dual targeting drugs.

Background And Purpose: Carbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner.

Material And Methods: The effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells.

Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation.

Background And Purpose: Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. The aim of this study was to evaluate the antitumor activity of a high CAIX-affinity indanesulfonamide (11c) combined with irradiation, compared with the general CA inhibitor acetazolamide (AZA).

Material And Methods: HT-29 carcinoma cells with or without (genetic knockdown, KD) CAIX expression were incubated with 11c/AZA under different oxygen levels and proliferation, apoptosis and radiosensitivity were evaluated.