NERATINIB – THE DUAL INHIBITOR

Introduction: The HER family of proteins

Epithelial growth factor is a common term in the field of biology, but what is not specificed is that this protein is a member of larger group of four protein with similar mechanisms and structures. This family is called the HER series of proteins and are labeled logically as HER 1-4. Illogically this proteins are still referred to under their old names such EGFR (HER 1) or ErRB 2-4 (HER 2-4) in many articles in literature [1-4]. These proteins function as a signaling mechanism across the cell membrane and they achieve this by having a receptor domain on the cell membrane exterior surface (head) connected to binding domains in the cytosole (tail). Binding of extracellular ligands to the “head” starts a chain reaction of events the first of which is the dimerization of the protein with another HER receptor. This caused structural changes transmitted through the “body” of the protein into the tail where Tyrosine binding domains are revealed. Kinase action will phosphorylate these domains activating them to binding of cytosolic ligands. Subsequently protein interaction transmits the signal from the original extracellular receptor all the way to the nucleus to initiate actions [5]

In terms of diseases that exhibit excessive proliferation and differentiation the inhibition of the EGFR (HER1) pathway can have a significant effect. Depending on which natural ligand is blocked as to which pathway is followed the end result can be decrease cell growth, altered gene transcription or apoptotic cell death. Inhibitors which block the EGFR pathway tend to be either monoclonal antibodies or derivatives of quinazoline. Neratinib is a 2^rd generation tyrosine kinase inhibitor (TKI) [6] which has a dual functionality, unlike Erlotinib and Gefitinib (1^nd generation TKI’s). Neratinib is potent against both EGFR and ErbB2 (or HER1 & 2) [7] and its advantage over erlotinib and gefitinib is that it is a irreversible inhibitor with activity against known mutations of the EGFR gene [8].

Neratinib: Properties and Availability

Neratinib was originally developed by Pfizer Plc under the developmental code HKI-272. However, Pfizer decided in 2011 to focus on several drug approvals outside of the cancer field and as a result development rights to Neratinib were passed to Puma Biotechnology (code PB-272). The central core of the Neratinib structure is an anilinoquinazoline, biological activity and specificity is dictated by a methoxy ether and an cyanyl substitution. Neratinib is a pan-inhibitor against the HER family with Neratinib IC50 of approximately 75 ± 15 nM registered for HER 1&2 [9]. Clinically there exists issues with Neratinib solubility; this molecule is very poorly soluble in water or alcohols and in DMSO only a maximum of 2 mg/ml can be reached. Formulation strategies for introduction of this compound into the mammalian system, therefore, remain a challenge. Fortunately the solid Neratinib stability means that it can be stored reliably at -20^oC or below with an expiration date of 2 years. However in solution Neratinib is unstable above pH 4, degrading in a cascade fashioned to a stable lactam form [10]. To buy Neratinib solid free base several reputable Neratinib suppliers are known with the Neratinib cost relatively stable. Neratinib price quotes for a 5 mg vial can range from $129 up to $240.

Neratinib: Preclinical Investigation

In 2004 HKI-272 or currently known as Neratinib was investigated in regard to its inhibitory role in the EGFR pathway, IC50 results indicated a potent inhibition of both HER1 & 2 (EGFR & ErbB2) [11]. Neratinib did demonstrate minor activity against KDR and SRC no other kinases demonstrated any significant effect. Cell culture SRB testing demonstrated anti-proliferation activity that correlated to cellular HER 2 over expression, HER2 over-expression is a common occurrence in both breast and lung. The effectiveness of this approach was demonstrated in when gefitinib and erlotinib resistant cells line where inhibited by using Neratinib [8]. Activity against lung and breast cancer was confirmed by Xenograft murine models, also established was the fact the clinical prognosis correlated with the compounds aqueous solubility [12-16]. Preclinical work established the effective range of Neratinib and proving its viability for phase 1 testing in lung and breast cancers [17-19].

Neratinib: Clinical Status                            

Neratinib breast cancer trials have been conducted at phase I and II level as a single therapy or as part of a combination with standard treatments and 25 Neratinib clinical trials are currently ongoing or near completion. In healthy subjects the pharmacokinetic and bioequivalence profile has been established and the effect of food on drug absorption investigated [20]. In a phase II trial with NSCLC patients a poor response was seen linked to a low bioavailability, this was suspected as being due to the dose limiting toxicity of Diarrhea [21]. In previously treated trastuzumab patients and in naïve HER2 positive patients a significant increase in progression free survival was seen with an overall clinical benefit of 36% [22].

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