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Research

Our group practises resistance-aware medicinal chemistry: we discover small molecules that remain effective when biology fights back, and that reach targets conventional inhibitors cannot. We design and synthesise all our compounds and lead the structure–activity relationship (SAR), computational design and physicochemical work; cellular, mechanistic and structural studies are carried out with long-standing collaborators.

Overcoming multidrug resistance with microtubule-targeting agents

Microtubule-targeting drugs are among the most widely used cancer therapies, but their success is often limited by multidrug resistance, especially overexpression of the P-glycoprotein (Pgp) efflux pump. Our first success was SSE15206, a pyrazolinethioamide that binds the colchicine site of tubulin, blocks spindle formation, causes apoptotic cell death and keeps its activity in cells that overexpress MDR-1. Its binding mode was later confirmed by an independent co-crystal structure. We have since found four further chemotypes, including microtubule destabilisers and stabilisers: a griseofulvin derivative, a selenadiazole (SSE1706), an azapodophyllotoxin (SSE1806) and a bis-amide (SSE1917). Several have been tested in tumour organoids with Dr Kevin Myant’s group at the University of Edinburgh. These hits are now in hit-to-lead optimisation, including replacement of the metabolically labile thioamide of SSE15206, supported by an AI-assisted modelling workflow for ranking new designs.

Reached microtubules: 0

An illustration, not data: the pumps (dark) throw a conventional drug back out, while a pump-evading compound reaches the microtubules at the centre.

  • Manzoor S, et al., Saleem RSZ*, Faisal A*. Sci. Rep. 2018, 8, 3305. doi
  • Firdous F, et al., Saleem RSZ*, Faisal A*. ACS Med. Chem. Lett. 2023, 14, 1369. doi
  • Iqbal S, et al., Faisal A*, Saleem RSZ*. Bioorg. Chem. 2024, 143, 107094. doi
  • Firdous F, et al., Saleem RSZ*, Faisal A*. Arch. Pharm. 2025, 358, e70087. doi
Kinase inhibitors and chemical probes

Approved kinase drugs address only a small fraction of the human kinome, and resistance mutations frequently erode their activity. With our collaborators we have reported inhibitors of FLT3, including a compound that overcomes D835Y-mediated resistance in acute myeloid leukaemia cells (awarded the 2021 Bashir-Alavi Award), and of Aurora kinase A. A differential scanning fluorimetry screen of our compound library has identified scaffolds that bind the understudied kinases NEK2, DRAK2 and CLK1. We are developing these into selective, co-crystallised chemical probes with Prof. Stefan Knapp’s group (Goethe University Frankfurt), to be released openly for the research community.

Choose a kinase to see what we have found.

  • Tariq MU, et al., Saleem RSZ, et al., Faisal A*. Br. J. Cancer 2021, 125, 966. doi
  • Furqan M, et al. J. Nat. Prod. 2022, 85, 1503. doi
  • Muddassar M, et al., Faisal A*. Bioorg. Med. Chem. 2025, 123, 118160. doi
Targeted protein degradation: molecular glues and PROTACs

Some cancer-driving proteins lack enzymatic activity or a defined binding pocket and are considered undruggable. Molecular glue degraders bring such a protein together with an E3 ubiquitin ligase so that the cell’s own disposal system destroys it. We established Pakistan’s first molecular glue degrader programme, targeting GSPT1 and oestrogen receptor α. Our cereblon-directed libraries, built on lenalidomide, pomalidomide and simplified aminoglutarimide scaffolds, are screened in HiBiT reporter cells, and wild-type and cereblon knock-out cells together with proteomics are used to find new degradable proteins. Looking ahead, we are building libraries for other E3 ligases, including DCAF15, DCAF16, RNF126 and MDM2, with the aim of disease- or tissue-selective degraders.

Cereblon GSPT1 Drag the glue into the gap
  • Saleem RSZ, Schwalm MP, Knapp S. Bioorg. Med. Chem. 2024, 105, 117718. doi
Antiviral drug discovery and open science

Pandemic preparedness needs antiviral chemical matter before an outbreak, not after. Within the NIH-funded READDI-AC AViDD Center at UCL, Dr Saleem coordinated medicinal chemistry against RNA-dependent RNA polymerase, helicase, protease and macrodomain targets in dengue, SARS-CoV-2 and chikungunya viruses. This work is run as open science, with compounds, data and structures released without restriction. We continue this strand with Prof. Matthew Todd’s group at UCL.

  • Oh H, et al., Saleem RSZ, et al. RSC Med. Chem. 2026, 17, 452. doi
  • Isaksson R, et al., Saleem RSZ, et al., Todd MH*. J. Med. Chem. 2026, 69, 2453 (ACS Editors’ Choice). doi
  • Group deposition of chikungunya virus nsP3 macrodomain–inhibitor structures, READDI-AC (PDB 7HIT). doi
Organic chemistry as an enabling science

Synthetic siderophores. With colleagues in the Department of Life Sciences, we develop synthetic siderophores to improve iron uptake in plants and human nutrition. The programme grew from internal seed awards into an HEC-NRPU grant (2025–27) and has attracted an industry partner.

Organoselenium and antimicrobial chemistry. Selenium-containing compounds developed with Prof. Claus Jacob (Saarland University) and others, including a source of new antimicrobial agents (RSC Med. Chem. 2025, 16, 3213).

Amyloid aggregation. Small molecules that modulate fibrillisation of amyloid-β and islet amyloid polypeptide (ACS Chem. Neurosci. 2021; Bioorg. Chem. 2019).

Organic optoelectronic materials. Donor–acceptor chromophores such as 2-aminoimidazolones, chalcones and quinoxaline carboxamides, studied by photophysics, electrochemistry and DFT.

Collaborative materials and synthesis. Ligands and building blocks for nanomaterials, sensing and catalysis, and C–H borylation and Suzuki coupling chemistry with the University of Hail.