Protein kinase inhibitors: breakthrough medicines and the next generation

Abstract

In this issue of Expert Opinion on Investigational Drugs, several protein kinases families and pathways underlying cancer and other diseases are reviewed and several small molecule inhibitors that are in clinical trials are further described. Highlights of these reviews and drug evaluations are summarized in this editorial.

Keywords::

• kinase inhibitor
• protein kinase
• proteins
• small-molecule

There are over 20 small-molecule protein kinase inhibitors currently approved for the treatment of human disease [1]. Inhibitors of protein kinases continue to be the focus of intense drug discovery efforts, especially in oncology. These life-changing drugs have emerged through the diligent efforts of basic, translational and drug discovery scientists [1]. Over the past 25 years delineation of signal transduction pathways emanating from protein kinases has demonstrated that these pathways are predominant information highways in cells. The aberrant activation of protein kinases in these pathways are key drivers of pathology. However, before drugs could be developed, daunting challenges in targeting kinases by small-molecule inhibitors had to be overcome. These included achieving selectivity against a large gene family and obtaining cellular potency in the face of high levels of cellular ATP. Milestones in the advancement of targeting protein kinases that addressed these challenges and led to kinase inhibitor drugs included: i) the unveiling of the kinome, ii) the elucidation of how protein kinases are regulated, iii) the elucidation of comparative structural biology of protein kinase target space and iv) the evolution of novel chemical inhibitors including designing inhibitors that exploited the conformational plasticity of kinases. These efforts led to proof-of-concept and breakthrough medicines such as imatinib (Gleevec®) and showed that inhibition of a critical protein kinase (in this case, Bcr-Abl kinase) could effectively translate to significant clinical success [2]. Gleevec completely transformed the treatment of chronic myeloid leukema (CML) from a death sentence into a chronic disease. However, early results from treatment with Gleevec revealed the specter of mutational resistance to the drug as a new challenge. The emergence of resistance to protein kinase inhibitors continues to be a key challenge in oncology drug discovery.

Achieving durable efficacy is one of the major challenges in targeting protein kinases in oncology. Major causes include: the lack of single driver mutations, the multitude of mutations in a single tumor, activation of redundant and alternative signaling pathways, genomic instability, and tumor heterogeneity. In addition, kinase signaling is critical to normal physiology which can present challenges for obtaining a therapeutic window especially in the context of combination therapy. Multi-targeted kinase inhibitors may be predominant on the list of approved inhibitors because of their potential to address some of these issues. However, this increased efficacy can sometimes be associated with additional safety liabilities. An additional problem is the pleiotropic nature of kinase signaling that is dependent on both cellular and tissue context. This complex biology presents challenges both from an efficacy and safety perspective. This is especially important in targeting kinases outside oncology where a high bar for safety and long-term treatment are often required. A notable milestone was recently achieved with the USA approval of tofacitinib (Xeljanz®) as the first small-molecule protein kinase inhibitor for an indication outside oncology.

In this issue of Expert Opinion on Investigational Drugs, several protein kinases families and pathways underlying cancer and other diseases are reviewed and several small-molecule inhibitors that are in clinical trials are further described. Highlights of these reviews and drug evaluations are summarized in this editorial.

The review by Nelson, Altman and Platanias [3] describes the mTOR pathway and its critical regulation of signals essential for mRNA translation of mitogenic genes and production of oncogenic proteins. Beyond rapalogs, which do not block mTORC2 and may only partially block mTORC1, a new generation of mTOR inhibitors are emerging that have dual mTORC1 and mTORC2 targeting. In fact blockade of both mTORC1 and mTORC2 have been shown to effect significant preclinical activity in many malignant cell types, including AML, Ph+ leukemias (CML and Ph+ ALL), lymphomas and some solid tumors. Early clinical studies are compelling with such dual mTOR inhibitors and suggest the potential for combination therapies.

The review by Larkin et al. [4] describes aberrant RAF signaling in human cancers, in particular BRAF as a key RAF family member that is commonly mutated, and the development of RAF-kinase inhibitors with respect to efficacy, modes of acquired resistance and the underlying mechanism of progression of pre-malignant RAS-mutant lesions that have been found for RAF-kinase inhibitors. Early clinical studies on more highly potent RAF-kinase inhibitors have shown success, especially as related to BRAF_V600 mutations, and for the treatment of advanced melanoma. Furthermore, the success of RAF-kinase inhibitors has highlighted the necessity of genotype-driven treatment selection for cancer patients and the critical importance of biomarkers in kinase drug discovery.

The review by Grant, Bose and Simmons [5] describes the roles of cyclin-dependent kinases (CDKs) in cell cycle progression regulation as well as in the control of cellular transcription, and their aberrant expression is found in many cancers. Preclinical studies have revealed that interference with cell cycle regulation could effectively induce apoptosis. Early clinical studies on pan-CDK inhibitors and, more recently, relatively selective inhibitors for specific CDKs, have shown encouraging efficacy across a wide spectrum of hematologic malignancies. Challenges in drug development remain in terms of off-target activities and rational combination with other cancer therapies to advance future CDK inhibitor drugs.

The review by Verstovsek and Tam [6] describes small-molecule inhibitors of the JAK family (e.g., ruxolinitib, SAR302503, lestaurtinib, pacritinib, CYT387, XL-019, LY2784544, BMS-911453, NS-018 and AZD1480). JAK inhibition has shown effectiveness in patients suffering from MPN, but these inhibitors have demonstrated less significant effects in modifying the underlying disease clone. Furthermore, the relationship between the specificity of JAK family inhibition and clinical efficacy and/or toxicity profile is poorly defined. Importantly, the success of the JAK inhibitors has increased interest in developing targeted therapies in myeloproliferative neoplasms.

The review by Lang and Voelkl [7] describes the role of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) when excessively expressed in the pathophysiology of several disorders including hypertension, obesity, diabetes, thrombosis, stroke, fibrosing disease, infertility and tumor growth. Preclinical studies have shown SGK1 inhibitors to reduce blood pressure of hyperinsulinemic mice and to counteract tumor cell survival. Targeting SGK1 may be clinically useful for the treatment of metabolic syndrome and tumor growth, and promising SGK1 inhibitors are being developed.

The review by Saad and Prada [8] describes how some known tyrosine-kinase inhibitors have promising anti-glycemic properties that may be correlated with molecular mechanisms underlying insulin resistance and beta-cell failure in type 2 diabetes mellitus. Specifically, imatinib, erltinib and sunitinib have been found to successfully treat some patients having both malignancies and diabetes. Although further investigation is warranted, the rationale for possible effects of such tyrosine kinase inhibitors to modulate insulin sensitivity as dysregulated by chronic low-grade inflammation, endoplasmic reticulum stress and alternations in gut microbiota may exist. Likewise, such tyrosine-kinase inhibitors may modulate beta-cell function or beta-cell mass to provide a therapeutic effect in overcoming beta cell failure.

The drug evaluation by Rosenberg and Mathew [9] describes lessons learned from targeting the platelet-derived growth factor (PDGF) receptor pathway in prostate cancer relative the known potent PDGF receptor kinase inhibitory properties of imatinib. Despite promising studies in preclinical models, imatinib has shown ineffectiveness to treat men with prostate cancer in clinical testing and, furthermore, implicate a negative correlation in terms of possibly accelerating advanced form of the disease and antagonism of taxane therapy. Indeed, a greater understanding of biological pathways through which PDGF and PDGF receptor fulfill a homeostatic role in men with metastatic prostate cancer is warranted as suggested from these clinical investigations.

The drug evaluation by King and Lee [10] describes clinical studies on the highly potent vascular endothelial growth factor (VEGF) receptor kinase inhibitor axitinib in patients with non-small cell lung cancer to further understand the role of angiogenesis in tumorigenesis. The mechanism of action, pharmacology, metabolism and preclinical as well as current clinical data is described. Such clinical studies use histology and early tumor response as an enrichment strategy to select patients that may benefit from drug treatment as well as permit the exploitation of tumor vasculature and other properties that might improve cytotoxic chemotherapy treatment.

The drug evaluation by Derenzini and Younes [11] describes the rationale underscoring the development of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways relative to being aberrantly activated in lymphoma to cause cell survival/proliferation and immune evasion. Pacritinib is the first and only JAK inhibitor that has been evaluated in patients with relapsed lymphoma, and it has demonstrated safety and proof-of-principle from early clinical studies in a variety of myeloproliferative neoplasms and lymphoma histologic types. The safety profile of Pacritinib suggests potential opportunity for combination with chemotherapy or other drugs (e.g., Bcl-2 family inhibitors, MEK inhibitors and HDAC inhibitors).

The drug evaluation by Solmo and Scher [12] describes the preclinical studies of the novel Src family kinase inhibitor dasatinib to inhibit breast cancer cell growth, invasiveness and metastases as well as clinical testing as a single agent and in combination with chemotherapy and anti-hormonal agents. Because the side effect profile of dasatinib is more advantageous than traditional chemotherapy, it may provide an advantage over traditional therapy in this setting. Studies are ongoing to find specific molecular markers that may predict response to dasatinib.

In conclusion, there continues to exist an extraordinary effort to advance protein kinase inhibitors for an increasing number of compelling protein kinase targets that have been correlated with disease pathways for unmet medical need. Major success in protein kinase inhibitor drug development has been realized within cancer therapy to date. Because of the vast number of protein kinases, the understanding of specificity, whether extremely narrow or slightly broader, is critically important to defining both efficacy and safety. Protein kinase system-based research is a key to determine the tractability of such target space to small-molecule inhibitors, including in-depth knowledge of both their chemical and biological properties [13]. Nevertheless, translation of preclinical models to clinical testing has shown that an incomplete understanding of protein kinases in terms of disease mechanisms exists and will be an important challenge to the development of the next generation of protein kinase inhibitors. Iclusig^™ [13] exemplifies a next generation imatinib-inspired drug which, using a unique design, circumvents the clinical resistance caused by known BCR-Abl mutations (including the infamous T315I gatekeeper mutation) [14]. This drug was very recently given accelerated approval based, in part, on significant benefit to patients who otherwise may not overcome such protein kinase mutational resistance.

Declaration of interest

TK Sawyer is employed by Aileron Therapeutics and JC Wu is employed by GlaxoSmithKline PLC. None of the remaining authors have any competing interests to declare and no funding was received in the preparation of this article. T Sawyer is the Guest Editor of this issue and has no additional competing interests to declare with regards to this article or any other in this issue.