Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

Abstract

The course of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) therapy has improved impressively. The Food and Drug Administration (FDA) has approved crizotinib (Xalkori, Pfizer) as a first-in-class tyrosine kinase inhibitor (TKI) that demonstrated a substantial objective response rate (ORR) and remarkable progression-free survival (PFS). However, acquired resistance to crizotinib is still a major concern especially as the central nervous system (CNS) remains the most common sites of relapse. To combat disease resistance, limited PFS and poor CNS exposure exhibited by crizotinib (Xalkori, Pfizer) led to the discovery of numerous next generation ALK-TKIs and surprisingly most of them are 2,4-Diarylaminopyrimidine Analogues (DAAPalogues). To date, DAAPalogues have been investigated extensively to display their superior potency against numerous kinase targets especially ALK/ROS1. This review describes hit-to-drug evolution strategies, activity spectra, milestones related to medicinal chemistry discovery efforts and scalable synthetic pathways of clinically emerging DAAPalouges which are either progressing as investigational or preclinical candidates. In addition, the significance of DAAPalogues to treat the patients with ALK⁺-NSCLC in clinical settings has been detailed. This review is beneficial for medicinal chemists and researchers contributing to discovering ALK-TKIs to overcome existing issues related to DAAPalouges in the drug discovery process.

Fig. 1. An overview of ALK in cancer and schematic summary of ALK overexpression, point mutations, and fusions in ALK positive cancer.

Fig. 2. The anaplastic lymphoma kinase receptor tyrosine kinase. (A) Schematic representation of pleotrophin (PTN) bound ligand activated anaplastic lymphoma kinase (ALK) receptor signalling. (B) Constitutively active ALK receptor signalling due to EML4 fusion. The fusion arises due to paracentric inversion between EML4 and ALK genes located in the short arm of chromosome 2. EML4-ALK translocation is thought to lead to the constitutive activation of oncogenic signaling through multiple pathways such as PI3K/Akt, JAK/STAT, and RAS/RAF/MEK/ERK. Aberrant activation of PI3K-Akt initiate mTOR, FOXO and GSK3β signalling which lead to survival and proliferation of tumour cells. PI3K/Akt activation also lead to MEKK2/3/MEK5/ERK5 pathway which subsequently promote the expression of the oncogene MYCN. The STAT3 signaling pathway has shown a key role in NPM-ALK mediated alteration however the significance of STAT3 activation in EML4-ALK⁺-NSCLC is unclear. ALK has also been shown to phosphorylate PLCγ to mediate its mitogenicity. (mTOR; mechanistic target of rapamycin, S6K; ribosomal S6 kinase, TD; trimerisation domain, TAPE; tandem atypical propeller domain, MAM; meprin, A5 protein, and protein tyrosine phosphatase Mu domain).

Fig. 3. FDA approved ALK inhibitors with substantial impact in the field of medical oncology with reported point mutations to drug resistance. (Only most critical mutations are shown. The mutations written in blue are most frequent and critical.)

Fig. 4. Novel, potent and selective DAAPalogues as ALK inhibitors.

Scheme 1. The strategic development of brigatinib (Alunbrig™, AP26113) (5) from a SRC inhibitor (AP23464).

Scheme 2. Medicinal chemistry discovery pathway of brigatinib.

Scheme 3. Summarized layout of NVP-TAE684 DAAPlouge and evolution of ceritinib.

Scheme 4. Pilot plant and scalable synthesis of CEP-28122 (17).

Scheme 5. The strategic development of CEP-37440 from (12).

Scheme 6. Pilot plant synthesis of CEP-37440 DAApalouge to provide clinical supplies.

Muhammad Latif

Zaman Ashraf

Sulman Basit

Abdul Ghaffar

Muhammad Sohail Zafar

Aamer Saeed

Sultan Ayoub Meo