Ack1 small molecule inhibitor AIM-100 

Mahajan K et al. Prostate.2010(Manuscript in press)

Synthesis of AIM100 from comercially available compound 1. (a) Ac2O, HCOOH, 60ºC, 6 hr, followed by slow addition of 1 at 0ºC then rt 12 hr, 90%; (b) AcOH, microwave heating at 200ºC, 60 min, 75%; (c) POCl3, 55ºC, 2 hr, under argon, 100%; (d) (S)-(+)-Tetrahydrofurfurylamine, EtOH, reflux, 5 hr, 87%.

 

While tyrosine kinase inhibitors or TKIs have emerged as new drugs for treatment of variety of tumors, TKIs display limited efficacy in certain cancers, including prostate cancer. Collectively, data from various studies indicates that inhibition of one Receptor tyrosine kinase (RTKs) may not be sufficient for the most tumor regression. Since Ack1 is able to integrate signals from various RTKs, Ack1 inhibitors could effectively block signal from multiple RTKs and thus would have significant anti-proliferative effects in breast, ovarian, pancreatic, lung and prostate cancer patients.

Elucidation of Ack1’s role in various cancers lead to screening efforts that resulted in identification of a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3- d]pyrimidine. We synthesized 4-amino-5,6-biaryl-furo[2,3-d]pyrimidine (renamed as AIM-100) and found that it is highly selevtive. Interestingly, AIM-100 suppressed not only suppressed both Ack1 Tyr284- and AR Tyr267-phosphorylations but also blocked AR recruitment to promoters/enhancers of AR-target genes, e.g., PSA, TMPRSS2, and NKX3.1. Further, AIM-100 inhibited the growth of prostate cells by causing cell cycle arrest in G0/G1 phase suggesting that targeting Ack1 may be an unique therapeutic strategy to inhibit androgen-independent AR activity.