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Kinase Inhibitors in Cancer

Authors: Chip Norwood & Oleg Kolupaev

Today, we are here with another post covering kinase inhibitors specifically related to cancer. We will cover several topics within this post, including: 1) the impact of cancer on human health, 2) a general overview of kinase inhibitors, 3) types of kinase inhibitors, and 4) clinical and commercial significance of these therapeutics.

Impact of Cancer on Human Health

According to the National Cancer Institute (NCI) analysis in 2018, an estimated 1.8 million new cases of cancer will be diagnosed in the United States (US) and 609,000 people will die from this disease.1 The national expenditure for cancer care in the US alone in 2017 was $147.3 billion, which is expected to continually rise. Hence, it is no surprise that efforts toward finding a suitable solution to this disease have been made over many decades. Indeed, the scientific community has made significant strides and a multitude of therapies have been developed, for example, chemotherapy. Chemotherapy uses small molecules to combat cancer cells through a variety of mechanisms.

Introduction to Protein Kinases

            Protein kinases catalyze phosphorylation of various substrates (e.g. proteins) that usually contain tyrosine, serine, and threonine (Scheme 1).2-5 Specifically, the terminal phosphate of adenosine triphosphate (ATP) is transferred to tyrosine, threonine, and serine within substrates. Subsequently, this resultant phosphorylation initiates a plethora of events within the cell, for example, phosphorylation could mark a protein for degradation.

Scheme 1. General transformation performed by protein kinases.

Dysregulation of kinases has been found to play a major role in the development of cancer (i.e., tumor cell proliferation and survival).5 So, the elucidation of the intricate role of kinases in the progression of cancer spurred the development of inhibitors of these proteins.

Types of Protein Kinase Inhibitors

Mostly, kinases are targeted at the binding site of its endogenous ligand ATP. There is high conservation in this binding site among all kinases; that is, the conserved DFG (apartate-phenylalanine-glycine) and APE (alanine-proline-glutamate) motifs at the start and end of the activation loop.2-5  This activation loop can adopt a large number of conformations which yield the protein either catalytically active or inactive. Substrate binding is either allowed or inhibited based on the position of the activation loop, which is sometimes referred to either the DFG-in or DFG-out confirmation, respectively.

Inhibitors have been categorized based on their binding to kinases. We’ll go over type I–III inhibitors, their binding modes to kinases, and a historical timeline of FDA-approved kinase inhibitors.

Type I & II Inhibitors

Type I inhibitors are directly competitive with ATP and recognize a conformation of the kinase which can facilitate phosphorylation. Typically, these inhibitors consist of a heterocycle which occupies the purine binding site that interacts with hydrophobic region II and II (e.g., Figure 2A). Several examples of type I inhibitors include Bosutinib, Gefitinib, Vandetanib, and Erlotinib (Figure 2B).

Figure 2. A. ABL1 in complex with the type I ATP-competitive inhibitor PD166326.5 B. Select FDA-approved type I kinase inhibitors.

In contrast, type II inhibitors bind the inactive conformation of kinases or DFG motif oriented “out” (Figure 3A). These inhibitors possess a motif that further extends into an allosteric site form hydrogen bonding interaction with conserved residues including DFG. Examples of FDA-approved type II inhibitors include Sorafenib, Imatinib, and Ponatinib (Figure 3B).

Figure 3. A. ABL1 in complex with the type II ATP-competitive inhibitor Imatinib.5 B. Select FDA-approved type II kinase inhibitors.

Type III Inhibitors

These inhibitors typically have the most selectivity for a specific kinase due to occupying an allosteric site unique to the kinase it inhibits.4 This is an area of intense research which has culminated in two FDA-approved drugs Trametinib and Cobimetinib (Figure 4).

Figure 4. Select FDA-approved type III kinase inhibitors.

Protein Kinase Inhibitor Market

Protein kinases are key components of signaling pathways orchestrating a variety of processes inside the cells: from cell cycle to differentiation to metabolism. This class of enzymes is also often dysregulated in malignant cell transformation, autoimmune, and inflammatory conditions making them a promising target for drug development.

Since the historic approval of BCR-ABL inhibitor imatinib (Gleevec), more than 70 drugs targeting a diverse array of protein kinases have been developed over the past 20 years. The total size of this market in 2018 was estimated to be $46.4 billion and was expected to grow 4% annually. More than half of the approved protein kinase inhibitors on the market target a subclass known as tyrosine kinases. About 1/3 of the drugs were designed to inhibit activity of receptor tyrosine kinases (EGFR, PDGFR, HER2) and 2/3 target non-receptor tyrosine kinases (BCR-ABL, BTK, JAK).

Historically, most protein kinase inhibitors were developed for oncology indications; however, development and repurposing of these drugs for inflammatory diseases and other conditions have been pursued. It is almost impossible to capture all the developments in this market in our short article. Here, we would like to provide two snapshots of the state of the market and competition for (1) receptor tyrosine kinase inhibitors of epithelial growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) and (2) non-receptor tyrosine kinase inhibitors of Bruton’s tyrosine kinase (BTK) in several non-Hodgkin lymphomas.

Receptor TKI of EGFR in Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the second most common form of cancer among women and men in the US. There are two major types of lung cancer: non-small cell lung cancer (NSCLC, 84%) and small cell lung cancer (SCLC, 13%). To further stratify these two, groups clinicians use histology characteristics and biomarker expression of the tumor cells for categorization. Mutations in KRAS, EGFR, ALK, or BRAF are found in more than half of all lung cancers and play an important role in tumor biology. These mutated proteins serve as biomarkers in selection of targeted therapies.

EGFR was one of the early targets for tyrosine kinase inhibitors in solid tumors, including NSCLC. Two EGFR inhibitors were approved for NSCLC patients by the FDA in the early 2000s: Iressa (gefitinib) marketed by AstraZeneca and Terceva (erlotinib) marketed by Roche. Both drugs are still being used in clinic today and are listed as ‘recommended’ for NSCLC patients with EGFR mutations in National Comprehensive Cancer Network (NCCN) guidelines. Second-generation of EGFR inhibitors reached the market in 2010. Boehringer Ingelheim’s Gilotrif (afatinib) and Pfizer’s Vizimpro (dacomitinib) both offered improved progression-free and overall survival compared to first-generation drugs.

In 2018 AstraZeneca’s third-generation inhibitor Tagrisso (osimertinib) was approved as a first-line treatment for metastatic NSCLC with mutated EGFR based on a FLAURA phase III clinical trial. The study demonstrated improved overall survival compared to the Iressa and Terceva. Having secured a ‘preferred’ status for late-stage NSCLC harboring EGFR mutations, AstraZeneca is conducting clinical trials to expand Tagrisso’s indication for the treatment of patients at the earlier stages of the disease.

In the market, Tagrisso absolutely dominates the mutated EGFR TKI category for NSCLC. Major competitors are monoclonal antibody therapies in combination with legacy TKIs, or chemotherapy, as evidenced by the recent approval of Eli Lilly’s anti-angiogenic drug Cyramza (ramucirumab) in combination with Terceva.

Figure 5. Sales of EGFR inhibitors in NSCLC.

Non-receptor TKI in NHL

Non-Hodgkin lymphoma (NHL) is one of the most common lymphomas. According to the American Cancer Society it contributes to about 4% of all cancer cases in the US. BTK inhibition represents a targeted approach to treat several subtypes of  B-lymphoid NHL, namely: mantle cell lymphoma (MCL), chronic lymphoblastic leukemia (CLL), marginal zone lymphoma (MZL), Waldelstrom microglobulemia (WM).

The first BTK inhibitor Imbrubica (ibrutinib) was approved by the FDA for an aggressive subtype of NHL – mantle cell lymphoma in 2013. Subsequently, Abbvie/J&J expanded the drug’s therapeutic window for the most common subtype of NHL – CLL (2014) and later for WM and MZL. Today, Imbruvica is listed as a preferred drug for these indications in NCCN guidelines. This position in the clinic propelled the drug to blockbuster status with $7.24 billion in sales in 2019.

Several competing BTK inhibitors have emerged for MZ and CLL/SLL indications in recent years. These second-generation agents demonstrated a more favorable safety profile, particularly low rate of heart-related side effects in late-stage clinical trials.

AstraZeneca has received an FDA approval for Calquence (acalabrutinib) for MCL treatment in 2017. The label was expanded in November of 2019 to include treatment of patients with CLL after successful ASCEND and ELEVATE phase III clinical trials. AstraZeneca reported $162 million in sales for Caquence in 2019 and $193 million in the first half of 2020. Analysts expect sales for the drug to grow as the company continues to get approvals outside of the US. If clinical trials go well with Caquence in patients with CLL, AstraZeneca’s drug can potentially replace Imbruvica as a ‘preferred’ treatment. This event could further accelerate sales after 2021.

Competition in this treatment area will grow fierce once BeiGene’s Brukinsa enters the CLL/SLL market. Currently, the drug is approved for use as a second-line treatment for relapsed/refractory MCL in the US. The drug is being studied as a front-line therapy for patients with CLL/SLL and WM in late-stage clinical trials.

Figure 6. Sales of Imbruvica and Caquence.

References:

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