Helal, Helal Abdulghani; (2024) Design, modelling, synthesis, and evaluation of inhibitors of human MPP1 and KifC1, two potential targets to drug development in cancer chemotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Kinesins are a family of molecular motor proteins that travel unidirectionally along microtubule tracks (MT) to perform a diverse range of functions from intracellular transport to cell division. Several compounds that inhibit either of two mitotic kinesins M phase phosphoprotein 1 (MPP1) and kinesin family member C1 (KifC1) are potential candidates for drug development in cancer chemotherapy. Human MPP1 is an N-terminal motor that travel towards the MT (+) end of microtubules and is necessary for the completion of cytokinesis. Previous studies have shown that MPP1 is upregulated in various types of bladder cancer. Recently natural products originally from lichens known as depsidones, and ascochitine from Ascochyta pisi Lib and Ascochyta fabae Speg were found to inhibit MPP1. Based on these observations a series of related compounds were designed, synthesised, tested and modelled as inhibitors of MPP1. Although the chromenone and quinolone derivative compounds as ascochitine-based inhibitors are less active compared to the depsidones and ascochitine in MPP1 ATPase inhibition assays, they are synthetically accessible analogues that could be further derivatised and optimised in order to improve their biological activity. On the other hand, KifC1, is a C-terminal motor that cross-links with MTs during spindle assembly and move towards the MT (-) end. A set of small molecule fragments were identified using NMR-based screening, that formed the basis for a further structure-activity relationship study of the initial hits. A series of KifC1 inhibitor analogues were synthesized successfully based on the structures of the fragment hits. Molecular docking studies were also used to predict the binding affinity of the fragment analogues, suggesting fragment analogues may not compete with ATP and may interact with a potential allosteric binding site adjacent to the Mg-ADP binding pocket, which is located on the L5/α2/α3 regions of the protein. Most of the new fragment analogues that were tested showed weak binding to KifC1 in basal ATPase measurements, although partial inhibition was identified in some cases, suggesting that testing the remaining compounds is justified and that the compounds could be further improved in future studies. The work presented improves our understanding of the SAR requirements for inhibition of MPP1 and KifC1 and provides a series of potential routes to the development of more potent analogues.

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