{"id":14,"date":"2018-06-08T10:45:35","date_gmt":"2018-06-08T10:45:35","guid":{"rendered":"https:\/\/orgchem.lums.edu.pk\/?page_id=14"},"modified":"2026-10-27T17:31:10","modified_gmt":"2026-10-27T12:31:10","slug":"research","status":"publish","type":"page","link":"https:\/\/orgchem.lums.edu.pk\/index.php\/research\/","title":{"rendered":"Research"},"content":{"rendered":"\n<div class=\"rg\">\n<h2>Research<\/h2>\n<p class=\"lede\">Our group practises <strong>resistance-aware medicinal chemistry<\/strong>: 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\u2013activity relationship (SAR), computational design and physicochemical work; cellular, mechanistic and structural studies are carried out with long-standing collaborators.<\/p>\n\n<ul class=\"rg-themes\"><li class=\"t-mdr\"><a href=\"#mdr\"><b>Multidrug resistance<\/b><span>Microtubule agents active in resistant cancer cells<\/span><\/a><\/li><li class=\"t-kin\"><a href=\"#kinases\"><b>Kinase probes<\/b><span>Inhibitors and open probes for understudied kinases<\/span><\/a><\/li><li class=\"t-tpd\"><a href=\"#degraders\"><b>Protein degradation<\/b><span>Molecular glues and PROTACs beyond cereblon<\/span><\/a><\/li><li class=\"t-vir\"><a href=\"#antivirals\"><b>Antivirals and open science<\/b><span>Pandemic-preparedness chemistry with UCL<\/span><\/a><\/li><li class=\"t-enb\"><a href=\"#enabling\"><b>Enabling chemistry<\/b><span>Siderophores, selenium, materials<\/span><\/a><\/li><\/ul>\n<details id=\"mdr\" class=\"t-mdr\" open><summary>Overcoming multidrug resistance with microtubule-targeting agents<\/summary><p>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 <strong>SSE15206<\/strong>, 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\u2019s 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.<\/p>\n<div class=\"rg-lab\">\n<canvas id=\"rg-pump\" width=\"640\" height=\"400\" aria-label=\"Simulation: drug molecules entering a cancer cell with efflux pumps\"><\/canvas>\n<div class=\"rg-ctrl\"><div class=\"rg-seg\" role=\"group\" aria-label=\"Choose compound\"><button type=\"button\" data-drug=\"conv\" aria-pressed=\"true\">Conventional drug<\/button><button type=\"button\" data-drug=\"sse\" aria-pressed=\"false\">SSE15206<\/button><\/div><span class=\"rg-readout\">Reached microtubules: <b id=\"rg-bound\">0<\/b><\/span><\/div>\n<p class=\"rg-hint\">An illustration, not data: the pumps (dark) throw a conventional drug back out, while a pump-evading compound reaches the microtubules at the centre.<\/p>\n<\/div>\n<ul class=\"refs\">\n<li>Manzoor S, et al., <strong>Saleem RSZ<\/strong>*, Faisal A*. <em>Sci. Rep.<\/em> 2018, 8, 3305. <a href=\"https:\/\/doi.org\/10.1038\/s41598-018-21642-0\">doi<\/a><\/li>\n<li>Firdous F, et al., <strong>Saleem RSZ<\/strong>*, Faisal A*. <em>ACS Med. Chem. Lett.<\/em> 2023, 14, 1369. <a href=\"https:\/\/doi.org\/10.1021\/acsmedchemlett.3c00258\">doi<\/a><\/li>\n<li>Iqbal S, et al., Faisal A*, <strong>Saleem RSZ<\/strong>*. <em>Bioorg. Chem.<\/em> 2024, 143, 107094. <a href=\"https:\/\/doi.org\/10.1016\/j.bioorg.2023.107094\">doi<\/a><\/li>\n<li>Firdous F, et al., <strong>Saleem RSZ<\/strong>*, Faisal A*. <em>Arch. Pharm.<\/em> 2025, 358, e70087. <a href=\"https:\/\/doi.org\/10.1002\/ardp.70087\">doi<\/a><\/li>\n<\/ul>\n<\/details>\n<details id=\"kinases\" class=\"t-kin\"><summary>Kinase inhibitors and chemical probes<\/summary><p>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\u2019s group (Goethe University Frankfurt), to be released openly for the research community.<\/p>\n<div class=\"rg-lab\">\n<div class=\"rg-kin\" role=\"group\" aria-label=\"Kinase targets\">\n<button type=\"button\" data-k=\"NEK2\" aria-pressed=\"true\">NEK2<small>new hit<\/small><\/button><button type=\"button\" data-k=\"DRAK2\" aria-pressed=\"false\">DRAK2<small>new hit<\/small><\/button><button type=\"button\" data-k=\"CLK1\" aria-pressed=\"false\">CLK1<small>new hit<\/small><\/button><button type=\"button\" data-k=\"FLT3\" aria-pressed=\"false\">FLT3<small>reported<\/small><\/button><button type=\"button\" data-k=\"AURKA\" aria-pressed=\"false\">Aurora A<small>reported<\/small><\/button><button type=\"button\" data-k=\"CHK2\" aria-pressed=\"false\">Chk2<small>PhD work<\/small><\/button>\n<\/div>\n<p class=\"rg-kin-info\" id=\"rg-kin-info\" aria-live=\"polite\">Choose a kinase to see what we have found.<\/p>\n<\/div>\n<ul class=\"refs\">\n<li>Tariq MU, et al., <strong>Saleem RSZ<\/strong>, et al., Faisal A*. <em>Br. J. Cancer<\/em> 2021, 125, 966. <a href=\"https:\/\/doi.org\/10.1038\/s41416-021-01527-2\">doi<\/a><\/li>\n<li>Furqan M, et al. <em>J. Nat. Prod.<\/em> 2022, 85, 1503. <a href=\"https:\/\/doi.org\/10.1021\/acs.jnatprod.1c01222\">doi<\/a><\/li>\n<li>Muddassar M, et al., Faisal A*. <em>Bioorg. Med. Chem.<\/em> 2025, 123, 118160. <a href=\"https:\/\/doi.org\/10.1016\/j.bmc.2025.118160\">doi<\/a><\/li>\n<\/ul>\n<\/details>\n<details id=\"degraders\" class=\"t-tpd\"><summary>Targeted protein degradation: molecular glues and PROTACs<\/summary><p>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\u2019s own disposal system destroys it. We established Pakistan\u2019s first molecular glue degrader programme, targeting GSPT1 and oestrogen receptor \u03b1. 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.<\/p>\n<div class=\"rg-lab\">\n<svg id=\"rg-glue\" viewBox=\"0 0 640 360\" role=\"img\" aria-label=\"Interactive: drag the molecular glue between cereblon and the target protein\">\n<rect width=\"640\" height=\"360\" fill=\"var(--wash)\"\/>\n<g id=\"rg-e3\"><path d=\"M60 110 q60 -40 130 0 q30 40 0 90 q-20 50 -70 60 q-70 0 -80 -60 q-10 -60 20 -90z\" fill=\"var(--t-tpd)\" opacity=\".88\"\/><text x=\"120\" y=\"190\" text-anchor=\"middle\" fill=\"#fff\" font-family=\"IBM Plex Sans,sans-serif\" font-weight=\"600\" font-size=\"20\">Cereblon<\/text><\/g>\n<g id=\"rg-poi\"><path d=\"M470 100 q70 -10 100 40 q20 60 -20 110 q-50 30 -100 0 q-40 -40 -20 -100 q10 -40 40 -50z\" fill=\"var(--t-mdr)\" opacity=\".88\"\/><text x=\"510\" y=\"190\" text-anchor=\"middle\" fill=\"#fff\" font-family=\"IBM Plex Sans,sans-serif\" font-weight=\"600\" font-size=\"20\">GSPT1<\/text><\/g>\n<g id=\"rg-ubs\"><\/g>\n<rect id=\"rg-slot\" x=\"280\" y=\"150\" width=\"80\" height=\"60\" rx=\"10\" fill=\"none\" stroke=\"var(--muted)\" stroke-dasharray=\"6 6\"\/>\n<g id=\"rg-glue-mol\" tabindex=\"0\" role=\"button\" aria-label=\"Molecular glue. Press Enter to place it.\" style=\"cursor:grab\"><circle r=\"34\" fill=\"var(--paper)\" stroke=\"var(--ink)\" stroke-width=\"2\"\/><polygon points=\"0,-18 15.6,-9 15.6,9 0,18 -15.6,9 -15.6,-9\" fill=\"none\" stroke=\"var(--ink)\" stroke-width=\"2.5\"\/><\/g>\n<text id=\"rg-glue-msg\" x=\"320\" y=\"320\" text-anchor=\"middle\" fill=\"var(--muted)\" font-family=\"IBM Plex Sans,sans-serif\" font-size=\"17\">Drag the glue into the gap<\/text>\n<\/svg>\n<div class=\"rg-ctrl\"><button class=\"rg-small-btn\" type=\"button\" id=\"rg-glue-place\">Place the glue for me<\/button><button class=\"rg-small-btn\" type=\"button\" id=\"rg-glue-reset\">Start again<\/button><\/div>\n<\/div>\n<ul class=\"refs\">\n<li><strong>Saleem RSZ<\/strong>, Schwalm MP, Knapp S. <em>Bioorg. Med. Chem.<\/em> 2024, 105, 117718. <a href=\"https:\/\/doi.org\/10.1016\/j.bmc.2024.117718\">doi<\/a><\/li>\n<\/ul>\n<\/details>\n<details id=\"antivirals\" class=\"t-vir\"><summary>Antiviral drug discovery and open science<\/summary><p>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\u2019s group at UCL.<\/p>\n<ul class=\"refs\">\n<li>Oh H, et al., <strong>Saleem RSZ<\/strong>, et al. <em>RSC Med. Chem.<\/em> 2026, 17, 452. <a href=\"https:\/\/doi.org\/10.1039\/D5MD00772K\">doi<\/a><\/li>\n<li>Isaksson R, et al., <strong>Saleem RSZ<\/strong>, et al., Todd MH*. <em>J. Med. Chem.<\/em> 2026, 69, 2453 (ACS Editors\u2019 Choice). <a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.5c02354\">doi<\/a><\/li>\n<li>Group deposition of chikungunya virus nsP3 macrodomain\u2013inhibitor structures, READDI-AC (PDB 7HIT). <a href=\"https:\/\/doi.org\/10.2210\/pdb7hit\/pdb\">doi<\/a><\/li>\n<\/ul>\n<\/details>\n<details id=\"enabling\" class=\"t-enb\"><summary>Organic chemistry as an enabling science<\/summary><p><strong>Synthetic siderophores.<\/strong> 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\u201327) and has attracted an industry partner.<\/p>\n<p><strong>Organoselenium and antimicrobial chemistry.<\/strong> Selenium-containing compounds developed with Prof. Claus Jacob (Saarland University) and others, including a source of new antimicrobial agents (<em>RSC Med. Chem.<\/em> 2025, 16, 3213).<\/p>\n<p><strong>Amyloid aggregation.<\/strong> Small molecules that modulate fibrillisation of amyloid-\u03b2 and islet amyloid polypeptide (<em>ACS Chem. Neurosci.<\/em> 2021; <em>Bioorg. Chem.<\/em> 2019).<\/p>\n<p><strong>Organic optoelectronic materials.<\/strong> Donor\u2013acceptor chromophores such as 2-aminoimidazolones, chalcones and quinoxaline carboxamides, studied by photophysics, electrochemistry and DFT.<\/p>\n<p><strong>Collaborative materials and synthesis.<\/strong> Ligands and building blocks for nanomaterials, sensing and catalysis, and C\u2013H borylation and Suzuki coupling chemistry with the University of Hail.<\/p>\n<\/details>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>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\u2013activity relationship (SAR), computational design and physicochemical work; cellular, mechanistic and structural studies are carried out with long-standing collaborators. Multidrug [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"template-full-width.php","meta":{"footnotes":""},"class_list":["post-14","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/pages\/14","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/comments?post=14"}],"version-history":[{"count":4,"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/pages\/14\/revisions"}],"predecessor-version":[{"id":367,"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/pages\/14\/revisions\/367"}],"wp:attachment":[{"href":"https:\/\/orgchem.lums.edu.pk\/index.php\/wp-json\/wp\/v2\/media?parent=14"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}