Dual Ended HDAC-Bcl-2 Inhibitor Therapeutics (DEHBIT): A Continuous Flow Chemistry Approach to Next-Generation Polypharmacological Cancer Therapeutics
About the Project
Background and Scientific Rationale
Cancer remains one of the most significant global health challenges, characterised by complex, multifactorial disease mechanisms requiring equally sophisticated therapeutic strategies. While the past decade has seen remarkable progress in targeted therapies, it has become clear that sustainable treatment success requires simultaneous attack on multiple molecular pathways. Administering combinations of separate drugs — a 'cocktail' approach — is theoretically sound but practically problematic, generating compounded toxicity, pharmacokinetic incompatibilities, and poor patient compliance.
An elegant solution to this problem lies in pharmacophore hybridisation: the fusion of two or more pharmacologically active groups into a single molecular entity — a polypharmacological inhibitor — capable of targeting multiple pathways simultaneously. This project applies that principle to two clinically validated but individually insufficient therapeutic axes in cancer: inhibition of the Bcl-2 family of anti-apoptotic proteins, and inhibition of histone deacetylase (HDAC) enzymes.
Bcl-2 family inhibition is exemplified by the FDA-approved drug Venetoclax, used in haematological malignancies. HDAC inhibitors (HDACi) are similarly established in the clinic. Crucially, emerging clinical evidence demonstrates significant synergistic anti-tumour activity when these two classes are combined, particularly in leukaemias, lymphomas, and multiple myeloma — creating a compelling scientific rationale for a single dual-targeting molecule.
Our Preliminary Work
The supervisory team has established a potent platform of HDAC inhibitors using a novel modular three-component cascade synthesis approach. These compounds selectively target HDAC1, avoiding the off-target toxicity associated with pan-HDAC inhibition, and have demonstrated anticancer activity in vivo. Structurally, they conform to the canonical zinc-binding group (ZBG) : linker : capping group (CAP) HDACi pharmacophore — and critically, the CAP region is amenable to modification, providing an ideal anchor point for integration of a Bcl-2 family pharmacophore to produce a dual-targeting molecule.
The current synthesis relies on a high-pressure allene gas 'one-pot' multicomponent reaction, which, whilst effective for compound discovery, presents safety challenges and limits scalability. The strategic next step — and the core of this PhD project — is translation of this chemistry to a continuous flow platform.
The PhD Project
This project will pioneer a continuous flow chemistry approach to the synthesis of dual HDAC:Bcl-2 family inhibitors, integrating medicinal chemistry, computational molecular modelling and cancer pharmacology.
Training and Skills Development
The successful student will receive outstanding interdisciplinary training across:
- Continuous flow chemistry and green synthetic methods
- Medicinal and synthetic organic chemistry
- Computer-aided drug design and molecular modelling
- Cancer cell biology and pharmacological screening
- Biophysical techniques including TR-FRET and surface plasmon resonance (SPR)
- Drug development pipelines and translational research
The student will be embedded in a vibrant, collaborative research environment at Newcastle University, with direct access to partners at the University of Leeds (Prof Colin Fishwick) and industrial contacts through Newcastle University's Cancer Research Horizons alliance. Students will be supported to present at international conferences (e.g. AACR, EACR) and to develop publication records commensurate with a career in academic or industrial drug discovery.
Ideal Candidate Profile
We are seeking a highly motivated graduate with a strong undergraduate degree (2:1 or above, or equivalent) in Medicinal Chemistry, Chemistry, Chemical Biology, Biochemistry, or a closely related discipline. Experience or strong interest in synthetic chemistry and/or cancer biology is advantageous. Candidates should demonstrate scientific curiosity, laboratory aptitude, and the ability to work both independently and as part of a multidisciplinary team.
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