Auckland Cancer Society Research Centre
Synthesis and development of CSF-1R inhibitors
CSF-1, also known as macrophage (M)-CSF, is a hemopoietic growth factor for the mononuclear phagocyte lineage and the primary regulator of macrophage differentiation, proliferation and survival. Expression levels of CSF-1 and CSF-1R correlate with tumour cell invasiveness and adverse clinical prognosis in breast, ovarian and prostate cancers.
Macrophages switch between two main phenotypes M1 (pro-inflammatory and immunostimulatory) and M2 (anti-inflammatory and immunosuppressive). CSF-1R signalling pathway is known to promote recruitment of M2 macrophages to the tumour microenvironment. CSF-1 and CSF-1R promote tumour-associated macrophages (TAMs) which in turn promote tumour progression and metastasis. CSF-1R inhibition targets tumour stroma & tumour itself, preventing tumour growth and metastasis. Designing drugs that can inhibit CSF-1R would reprogram macrophages from M2 to M1 phenotype. Our research group has been developing novel CSF-1R inhibitors as anticancer agents.
In this project, you will be involved in the chemical synthesis of inhibitors and their biological evaluation as outlined below:
(1) Chemical synthesis, characterization of compounds you make by NMR, LC-MS/MS
(2) In- vitro testing (mouse/human plasma stability, protein binding, microsomal stability)
Skills you will gain: Organic/medicinal chemistry in drug development - compound synthesis, purification (chromatography techniques) and structure identification (nuclear magnetic resonance (NMR) spectroscopy, high performance liquid chromatography/mass spectrometry) and the use of scientific data bases (Scifinder, Agilent MassHunter) and pharmacokinetic software (Phoenix WinNonlin).
New DNA minor groove alkylating agents for arming anticancer antibodies
Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics which have stimulated much interest. They have the unique ability to deliver cytotoxic-agents differentially to tumour cells limiting systemic toxicity. Duocarmycins are ultra-potent agents derived from a class of natural products and have the potential to surpass existing agents, however, are limited by poor solubility. Currently we are looking to synthesise and pre-clinically evaluate a series of novel duocarmycin-based analogues that address vital properties, and which are predicted to provide more effective ADCs.
During this 8 week research project, you will learn how to construct and apply synthetic methodology towards the development of such analogues and learn the key purification and characterisation methods that are required for each developmental synthetic step.
The preferred candidate should be highly motivated and have a passion for drug discovery and innovative science. While a background in chemistry would be an advantage, it is not essential.
New theranostic bifunctional agents for targeted cancer therapy
Dr Christian Miller
Faculty of Medical and Health Sciences
Project code: MHS007
Targeted anticancer drug delivery is a promising method to enable greater efficacy and safety of therapeutic agents. Antibody-drug conjugates (ADCs) have emerged as a powerful tool in this context. However, tumour cell selectivity and toxicity remain a significant problem in their advancement. Less than 1% of an administered ADC accumulates within target tumours with the remainder undergoing bio-distribution to normal tissues and organs which can induce broad toxicities. We are currently developing a new ADC system that could provide bifunctional theranostic capability for tumour localisation-imaging and treatment. It incorporates a Near IR (NIR)-absorbing heptamethine cyanine dye with high affinity towards organic anion transporter proteins (OATPs). OATPs are known to be upregulated/highly expressed on solid tumour cancer cells, and represent an additional biomarker for a duel selective drug-delivery approach mitigating off-target toxicity.
During this 8 week research project, you will learn how to construct and apply synthetic methodology towards the development of such conjugates and learn the key purification and characterisation methods that are required for each developmental synthetic step. The preferred candidate should be highly motivated and have a passion for drug discovery and innovative science. While a background in chemistry would be an advantage, it is not essential.