Abstract
The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.
Highlights
Deregulation of MYC-family oncogenes is associated with a poor prognosis and unfavorable survival of cancer patients.1 Amplification of MYC-family oncogenes has been observed in 28% cancers in The Cancer Genome Atlas (TCGA).2 Sustained MYC-family protein levels can initiate tumor formation, accelerate tumor progression, and help in tumor maintenance
Compounds 1−21 (Table 1) were prepared according to the general synthetic method depicted in Schemes 1 and 2
Based on the above results and the availability of different halogenated benzoic acid derivatives, we investigated the contribution of such substituents to cMYC/MYCN levels
Summary
Deregulation of MYC-family oncogenes (i.e., cMYC, MYCN, and MYCL) is associated with a poor prognosis and unfavorable survival of cancer patients. Amplification of MYC-family oncogenes has been observed in 28% cancers in The Cancer Genome Atlas (TCGA). Sustained MYC-family protein levels can initiate tumor formation, accelerate tumor progression, and help in tumor maintenance. Deregulation of MYC-family oncogenes (i.e., cMYC, MYCN, and MYCL) is associated with a poor prognosis and unfavorable survival of cancer patients.. Sustained MYC-family protein levels can initiate tumor formation, accelerate tumor progression, and help in tumor maintenance. Many MYCdriven metabolic changes such as glycolysis and glutaminolysis support the increased need of nucleic acids, proteins, and lipids during rapid cell proliferation.. Despite the pivotal role of MYC in normal tissue regeneration, several murine-based studies have supported MYC as a potential therapeutic target for cancers. A conditional transgenic mouse model for MYC-induced tumorigenesis demonstrated that brief inactivation of cMYC was sufficient to elicit sustained regression of transplanted osteogenic sarcoma cells, and knockdown of cMYC in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest and increased apoptosis, whereas nonstem glioma cells displayed limited dependence on MYC expression for survival and proliferation.
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