Auckland Cancer Society Research Centre

Development of novel near infra-red emitting heptamethine cyanine dyes-drug conjugate for treatment of glioblastoma

Supervisor

Dr. Jiney Jose

Faculty of Medical and Health Sciences

Project code: MHS002

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common and most malignant of glial tumours which begins within the brain. It has a very poor prognosis with a median survival period of 12 -15 months. The project aims to explore novel near infra-red emitting heptamethine cyanine dyes for inhibition of brain cancer cell lines. Heptamethine cyanine dyes (HMCDs) are reported to possess cytotoxic properties and therefore serves as an attractive scaffold for development of target specific anticancer drugs. Certain class of HMCDs are able to cross the blood brain barrier (BBB). Many drugs fail to cross the BBB and therefore unable to reach the brain tumour for effective treatment.  There are also reports of some heptamethine cyanine dyes showing selectivity towards cancer cells compared to normal cells. This selectivity is attributed to several biological phenomena acting together but not limited to events such as activation of organic anion-transporting polypeptides on cancer cell membranes, hypoxic tumour microenvironment and mitochondrial membrane potential disruption in cancer cells. Synthetic modification of HMCDs could result in compounds suitable for treatment of GBM. Our initial synthetic effort has resulted in compounds with good activity against patient derived brain cancer cell lines. We are planning to further explore the structure activity relationship of these compounds to improve their potency and BBB crossing ability. Project will involve syntheses of various analogues of HMCDs aimed at targeting brain cancer cell lines in a modern synthetic chemistry laboratory. It will involve syntheses, purification and characterisation of analogues and testing them for activity in various brain cancer cell lines. Background in chemistry is an advantage but not essential.

Light activated cyanine dye-antibiotic conjugates for treatment of bacterial infections

Supervisor

Dr. Peter Choi, Dr. Jiney Jose

Faculty of Medical and Health Sciences

Project code: MHS003

Antibiotic resistance is one of the biggest threats to global health and development today. Although antibiotic resistance can occur naturally, increase in misuse of antibiotics is accelerating the process globally. An alternative novel method to kill bacteria is using dye molecules as photosensitizers which become excited when illuminated with light. This causes photosensitizers to convert oxygen into reactive oxygen species that attack and kill the bacteria. This project aims to explore novel near infra-red emitting heptamethine cyanine dye as conjugates to antibiotics for inhibition of various bacterial cell lines. Heptamethine cyanine dyes (HMCDs) are known to generate reactive oxygen species when illuminated with specific wavelength of light and by conjugating them with various class of antibiotics, it would enhance their bactericidal properties. Project will focus on syntheses of various analogues HMCD-antibiotic conjugates aimed at treating bacterial infections in a modern synthetic chemistry laboratory. It will involve syntheses, purification and characterisation of analogues and testing them for activity in various bacterial cell lines. Background in chemistry is an advantage but not essential.

Synthesis and development of CSF-1R inhibitors

Supervisor

Swarna A. Gamage, Jagdish Jaiswal

Faculty of Medical and Health Sciences

Project code: MHS006

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-1 has direct effects on tumour growth & release of tumour-derived inflammatory mediators. 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.

Hypoxia activated prodrugs related to the PARP inhibitor talazoparib

Supervisor

Dr. Benjamin Dickson, Assoc. Prof. Michael Hay

Faculty of Medical and Health Sciences

Project code: MHS007

Talazoparib is the most potent PARP inhibitor currently in clinical use. There is evidence that its ability to ‘trap’ PARP on DNA contributes significantly to its efficacy. Trapping of PARP has been suggested as one of the means by which PARP inhibitors induce off target (normal cell) toxicity. Hypoxia activated prodrugs (HAPs) provide targeted activation of a PARP inhibitor within tumours, reducing off target toxicity. This medicinal chemistry project aims to synthesise analogues of talazoparib and prepare HAPs of these analogues.

Aims:

  • Use molecular docking to design new analogues of talazoparib suitable for prodrug synthesis
  • Prepare analogues of talazoparib
  • Prepare prodrugs of the aforementioned analogues

New DNA minor groove alkylating agents for arming anticancer antibodies

Supervisor

Dr. Christian Miller, Dr. Moana Tercel

Faculty of Medical and Health Sciences

Project code: MHS010

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. Your role in this project will be to conduct parallel studies towards the synthesis of new duocarmycin agents that explore alternative tether points for conjugation to a linker-antibody. The preferred candidate should be highly motivated, have a passion for drug discovery and development, and innovative science. Some experience working in a chemistry laboratory is preferable. You will gain experience in the design, synthesis, purification methods, and characterisation of new cytotoxic analogues for ADC advancement, as well as having the opportunity to participate in a multidisciplinary and collaborative research environment at the Auckland Cancer Society Research Centre.

A new approach to developing novel immunosuppressive agents

Supervisor

Dr. Julie Spicer, Dr. Jiney Jose

Faculty of Medical and Health Sciences

Project code: MHS014

The goal of our research programme is to inhibit the activity of a protein called perforin that is critical to the operation of the immune system. Our team involves a multi-disciplinary, multi-national collaboration between institutes in New Zealand, Australia, USA and Germany. The aim is to specifically and transiently block the function of perforin in order to develop a highly selective immunosuppressive drug that avoids the toxic effects of conventional treatments. We have already identified molecules that prevent rejection of transplanted bone marrow cells in mice and which protect against virally-triggered liver failure. This project will involve the design and preparation of new molecules for biological testing, and the use of assay data to feed back into the design of new improved immunosuppressive compounds. While a background in chemistry would be an advantage, it is not essential.

SKILLS:

  • Medicinal and synthetic chemistry
  • Use of instrumentation (NMR, HPLC, MS)
  • Data analysis
  • Use of various database software (Scifinder, Reaxys, CDD, Data Warrior)
  • Experience of working on an multi-disciplinary project
  • Scientific writing