REVIEWS Kinase drug discovery 20 years after imatinib: progress and future directions Philip Cohen 1 ✉ , Darren Cross 2 ✉ and Pasi A. Jänne 3 ✉ Abstract | Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non- cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery. Protein kinases In 2001, the first kinase inhibitor, imatinib, received FDA entered clinical trials in 1998, changed the perception Enzymes that catalyse transfer approval, providing the catalyst for an article with the of protein kinases as drug targets, which had previously of the γ- phosphate of ATP provocative title ‘Protein kinases — the major drug tar- received scepticism from many pharmaceutical com- to amino acid side chains in gets of the twenty- first century?’1. Imatinib inhibits the panies. Since then, hundreds of protein kinase inhibi- substrate proteins, such as serine, threonine and tyrosine Abelson (ABL) tyrosine kinase, which is expressed as a tors have been developed and tested in humans and, at residues. deregulated fusion protein, termed BCR–ABL, in nearly the time of writing, 76 have been approved for clinical all cases of chronic myeloid leukaemia (CML)2 and is use, mainly for the treatment of various cancers (FiG. 1; produced by a chromosome rearrangement that fuses Supplementary Table 1). The clinical application of the genes encoding the breakpoint cluster region protein kinase inhibitors has also been facilitated by large- scale (BCR) and ABL to form the Philadelphia chromosome. genomic efforts, which have identified subsets of cancers Although fasudil (an inhibitor of RHO-dependent pro- that can potentially be treated with a kinase inhibitor9,10. tein kinases) and rapamycin (sirolimus, an inhibitor of In this review marking the 20th anniversary of the the protein kinase TORC1) were approved earlier than approval of imatinib, we discuss the progress that has 2001 (Supplementary Table 1), these compounds were been made in improving the development of potent developed and approved without knowledge of the and specific small- molecule tyrosine kinase inhibitors identity of their target proteins. Imatinib was therefore (TKIs) and in combatting the problem of resistance to the first drug that was developed by targeting a specific these inhibitors in cancer therapy, the potential of com- protein kinase to treat a disease to be approved. bination therapies, the efficacy of kinase inhibitors in At the time of writing the article highlighted above, the clinic compared with other types of therapy and the small-molecule inhibitors of the tyrosine kinase activity of exploitation of kinase inhibitors for the treatment of dis- the epidermal growth factor receptor (EGFR) were on the eases other than cancer. Finally, we try to predict what cusp of approval and, as predicted, two such inhibitors — the future of kinase drug discovery will be over the next gefitinib (also known as Iressa) and erlotinib (also 20 years. 1MRC Protein known as Tarceva) — were approved soon afterwards Phosphorylation and for the treatment of non-small- cell lung cancer (NSCLC) Lessons from imatinib, gefitinib and erlotinib Ubiquitylation Unit, School of Life Sciences, University of (FiG. 1). These drugs were originally designed to inhibit When imatinib was first discovered, it was not initially Dundee, Dundee, UK. the wild- type version of the EGFR, which had been given high priority for further development because of 2AstraZeneca, Cambridge, UK. shown in the late 1980s to be overexpressed in many can- the low incidence of CML. Consequently, it only entered 3,4 3Lowe Center for Thoracic cer types and to be associated with a poor prognosis . clinical trials 5 years later. So why did imatinib become Oncology, Dana Farber However, it was the discovery that profound tumour one of the world’s most commercially successful drugs Cancer Institute, Harvard sensitivity to these inhibitors was associated with par- with peak sales of US$4.6 billion in 2012 before it went University, Boston, MA, USA. ticular activating EGFR mutations that are present in off patent in 2015? The first reason is that imatinib trans- ✉e- mail: p.cohen@ 10–15% of Western and 30–50% of Asian patients with formed CML from a rapidly fatal disease to a managea- dundee.ac.uk; Darren.Cross@ 5–8 astrazeneca.com; pjanne@ NSCLC that ultimately led to the clinical use of these ble condition, so that CML is no longer a rare leukaemia, partners.org drugs in patients with EGFR mutations. with more than 100,000 patients now requiring imatinib https://doi.org/10.1038/ The success of these pioneering compounds, espe- daily to ensure their survival. It is indeed an irony that s41573-021-00195-4 cially the spectacular efficacy of imatinib as soon as it such a spectacular cancer therapy actually increases the NATURE REVIEWS | DRUG DISCOVERY VOLUME 20 | JULY 2021 | 551 0123456789();: REVIEWS More potent and specific second-generation inhibitors of ALK, ROS, RET and MET approved for lung cancer Second-generation HER2 inhibitors (neratinib and tucatinib) Improved next-generation BCR–ABL approved for breast cancer inhibitors (ponatinib, bosutinib and First PI3Kδ inhibitor radotinib) approved for CML that idelalisib approved for CLL inhibit many imatinib-resistant mutants VEGFR inhibitor tivozanib First combination therapy approved for renal cell carcinoma The JAK inhibitor tofacitinib approved exploiting two kinase for rheumatoid arthritis. First rationally inhibitors (dabrafenib plus CDK4/CDK6 inhibitor trilacyclib designed kinase inhibitor approved for trametinib) approved for approved for lung cancer a disease other than cancer malignant melanoma First PI3Kα inhibitor Third-generation apelisib approved Approval of multitargeted EGFR inhibitors for breast cancer kinase inhibitors for renal cancer osimertinib and olmutinib First specific FGFR Approval of the first VEGFR inhibitors targeting approved for inhibitor (erdafitin- rationally designed angiogenesis approved for EGFR-T790M ib) approved for kinase inhibitor (imatinib) solid tumours (renal, thyroid resistant lung bladder cancer for CML and GIST and colorectal cancer) cancer 2001 2002 2003 2005 2006 2007 2009 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 Approval of the Approval of the first First kinase inhibitors first EGFR TKIs for ALK inhibitor First CDK4/CDK6 inhibitors targeting mutant MET lung cancer crizotinib for lung approved for breast cancer (capmatinib, tepotinib) (gefitinib, erlotinib) cancer approved for lung cancer First kinase inhibitors able to cross Approval of first JAK the blood–brain barrier approved Kinase inhibitors targeting inhibitor ruxolitinib (osimertinib, lorlatinib) mutant RET (selpercatinib for myelofibrosis and pralsetinib) approved for lung and thyroid cancers Next-generation inhibitors Approval of first RAF Third-generation kinase inhibitor First kinase inhibitor of BCR-ABL (dasatinib and inhibitors vemurafenib (osimertinib) approved as the first line approved for early-stage nilotinib) approved for CML and dabrafenib for treatment for EGFR mutant lung cancer adjuvant treatment of lung malignant melanoma; cancer following surgery Approval of the HER2/EGFR rational development First third-generation ALK inhibitor (osimertinib) inhibitor lapatinib for of the first Ser/Thr (lorlatinib) approved for the treatment breast cancer kinase inhibitors of crizotinib-resistant lung cancer MEK inhibitor selumetinib approved for treatment of children with The first allosteric kinase inhibitor (trametinib), neurofibromatosis type 1 approved for malignant melanoma First covalent kinase inhibitors approved; First NTRK inhibitors second-generation EGFR inhibitor afatinib for approved for the treatment lung cancer, BTK inhibitor ibrutinib for of thyroid, salivary and other haematological cancers solid tumours Fig. 1 | Timeline depicting important events in the development and approval of kinase inhibitors over the past 20 years since imatinib was approved for treatment of CML in 2001. Events involving tyrosine kinases are in pink boxes, those involving serine/threonine-specific protein kinases are in blue boxes and those involving phosphatidylinosi- tol 3-kinases (PI3Ks) are in grey boxes. BTK, Bruton’s tyrosine kinase; CML, chronic myeloid leukaemia; CLL, chronic lymphocytic leukaemia; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal tumour; NTRK, neurotrophic receptor tyrosine kinase; TKI, tyrosine kinase inhibitor. incidence of cancer because it manages, but does not was needed compared with most drugs, as there were cure, the disease. no other treatment options for patients with CML. Thus, Second, imatinib was found to be equally effective the huge costs of drug development were minimized. in treating other rare cancers, such as gastrointestinal The remarkable efficacy of imatinib in CML can also tumours (GIST), because it inhibits not only BCR–ABL be attributed to another factor. First, like other haema- Polypharmacology but also two other protein kinases (the KIT and PDGF