Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Abstract

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.

Polypharmacology-based ceritinib repurposing using integrated functional proteomics

“…Consistent with the gene silencing, the dual CAMKK2/AMPK inhibitor compound C did not synergize with paclitaxel. In addition, combination of paclitaxel with the CDK4/6 inhibitor ribociclib, which has no activity against RSK1/2, IGF1R, or FAK1, 37 did not exhibit synergy, whereas the FAK1/RSK/IGF1R inhibitor CEP-37440 38 strongly synergized with paclitaxel (Supplementary Fig. 7e–f).…”

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

“…To this end, the drug designing strategy stemmed from our literature survey has demonstrated that ceritinib (LDK-378, 2 nd -generation ALK/ROS1 inhibitor Zykadia®, Novartis), brigatinib (Alunbrig™, AP26113), NVP-TAE684, Cephalon 2812, Cephalon 1, and CEP-37440 comprised of DAAP-motif are clinically novel ALK-TKIs. 87,[108][109][110][111][112][113] It is signicant to note that on DAAP template chloro (Cl) substituent have been installed as an optimal substituent at C-5 position of pyrimidine which in most of the DAAPlouges interacts with ALKL1196 gatekeeper residue. The designing strategies, biological characteristics, therapeutic exploration, and clinical data of DAA-Palogues as ALK inhibitors is well-detailed in literature.…”

“…Recently reported investigations related to CEP-37440 has led to enhanced metabolic stability, imperious pharmacokinetic features, and adequate in vitro activity in clinically described resistance mutations. 112 In the following section, medicinal chemistry efforts related to early discovery of CEP-37440 (12) and clinical developments are discussed.…”

“…A single dose of novel CEP-28122 (17) given orally at 30 mg kg À1 revealed more than 90% inhibition of NPM-ALK phosphorylation in the tested NPM-ALK positive ALCL Karpas-299 (17) was well tolerated and at both dosing regimens neither evident toxicity nor a signicant body weight loss was observed. 112 Dose-dependent antitumor activity potential was also assessed in NPM-ALK-positive ALCL and EML4-ALK-positive NSCLC tumor xenogras in mice wherein CEP-28122 (17) was administered orally. It showed complete or near to complete tumor regression by following a therapy at a dose of 30 mg kg À1 b.i.d.…”

“…From the combination of entire favorable biological and pharmaceutical properties, the CEP-28122 (17) was discovered as a preclinical candidate. 112 The PK characteristics of novel analogs (13)(14)(15)(16)(17)(18)(19) discovered during the strategic development of CEP-37440 from (12) are presented in Table 3.…”