Brigatinib: Development History and Preclinical Studies

General Description

Brigatinib is a vital treatment for non-small cell lung cancer patients with EGFR and ALK genetic mutations. Approved by the FDA in 2017, its development involved significant milestones, including successful clinical trials and FDA acceptance. The drug's chemical features enable it to effectively inhibit ALK, with an MIC value of 0.6 nmol/L. Brigatinib's unique structure allows it to bind to the ATP attachment site of ALK, demonstrating potent activity against mutations, including those resistant to other ALK inhibitors. These features position Brigatinib as a robust and selective ALK inhibitor, offering hope for non-small cell lung cancer patients facing resistance to traditional treatments.

Figure 1. Brigatinib

Development history

Brigatinib, marketed under the brand name Alunbrig, is a crucial treatment for non-small cell lung cancer (NSCLC) patients with EGFR and ALK genetic mutations. Approved by the FDA on April 28, 2017, Brigatinib is manufactured by Takeda Pharmaceuticals, USA., Inc. Administered orally in tablet form at a dosage of 90 mg once daily, it targets patients resistant to other ALK inhibitors. The developmental history of Brigatinib showcases significant milestones. In April 2015, ARIAD Pharmaceuticals provided updates on ongoing clinical trials for NSCLC patients with ALK genetic rearrangements. By April 2016, a phase 1/2 trial was successfully completed, leading to the submission of a New Drug Application to the FDA on June 17, 2016. The application process concluded on August 30, 2016, with FDA acceptance announced on October 31, 2016. Finally, on April 28, 2017, Takeda confirmed FDA approval for Brigatinib's market use, marking a critical advancement in lung cancer treatment. ¹

Preclinical studies

Drug discovery and chemical features

The discovery and chemical features of brigatinib have contributed to its potential as an effective ALK inhibitor. Initially, the challenge in drug discovery was due to ALK's structural similarity to insulin growth factor-1 receptors. However, research efforts identified molecules capable of selectively inhibiting ALK without affecting insulin growth factor-1 receptors. This led to the discovery of brigatinib, which demonstrated an MIC value of 0.6 nmol/L. In animal studies, oral administration of brigatinib to lung cancer-afflicted mice showed complete antitumor effects at doses ranging from 50 to 100 mg/kg. These doses also effectively targeted ALK in rats without compromising selectivity. The chemical structure of brigatinib differs from crizotinib, with a bis-anilino-pyrimidine moiety replacing the amino-pyridine framework found in crizotinib. This unique structure provides a U-shaped platform that allows brigatinib to bind to the ATP attachment site of ALK. Brigatinib contains two NH2 groups attached to a phenyl ring, which is further connected to carbon 2 and 4. Additionally, an -OCH3 group and a chlorine atom on carbon number 5 contribute to its interaction with ALK. Another distinguishing feature is the presence of a dimethyl phosphine oxide (DMPO) moiety attached to the -NH2 group of the phenyl ring at carbon-4. This DMPO moiety is responsible for brigatinib's selectivity profile over ALK. Overall, the chemical features of brigatinib, such as expanded fluid solvency, decreased lipophilicity, and reduced protein binding, play a crucial role in its effectiveness as an ALK inhibitor. ²

Activity against mutations in ALK

Brigatinib demonstrates potent activity against mutations in ALK, making it a promising treatment for ALK inhibitor-resistant cases in non-small cell lung cancer patients. Research by Zhang et al. in 2014 and 2016 highlighted Brigatinib's efficacy in overcoming resistance to other ALK inhibitors. In an in vitro experiment using Ba/F3 cells, it was found that a concentration of 500 nmol/L of Brigatinib was effective in circumventing resistance observed with other ALK inhibitors. Furthermore, studies on cell lines with various mutagenic substances causing ALK resistance showed that Brigatinib outperformed other ALK inhibitors like alectinib and crizotinib, with a minimal inhibitory concentration (MIC) value of <200 nmol/L. Importantly, Brigatinib displayed selectivity against ALK mutant variants such as G1202R. These findings position Brigatinib as the most robust ALK inhibitor, offering hope for non-small cell lung cancer patients facing resistance to traditional treatments and potentially improving patient outcomes significantly. ³

Reference

1. Bedi S, Khan SA, AbuKhader MM, Alam P, Siddiqui NA, Husain A. A comprehensive review on Brigatinib - A wonder drug for targeted cancer therapy in non-small cell lung cancer. Saudi Pharm J. 2018;26(6):755-763.

2. Shakespeare W, Fantin V, Wang F, Kohlmann A, Liu S, Huang WS, Wang Y, Zou D, Thomas M, Li F, Qi J. Discovery of potent and selective orally active inhibitors of anaplastic lymphoma kinase (ALK) Cancer Res. 2009;69:3738.

3. Zhang S, Anjum R, Squillace R, et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016;22(22):5527-5538.

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