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| Type |
Symposium |
| Area |
Recent Trends in Drug Discovery and Technology |
| Room No. |
404호 |
| Time |
THU 14:00-: |
| Code |
MEDI-2 |
| Subject |
Discovery of tetrahydroisoquinoline ALK inhibitors and reversible BTK-non-ITK inhibitors |
| Authors |
김필호
한국화학연구원 의약화학연구센터, Korea |
| Abstract |
I. Crizotinib (Xalkori by Pfizer) was approved by the US FDA in 2013 to treat anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients. The patients treated with crizotinib always relapse usually in one year due to the development of drug resistance. Thus, efforts to develop second-generation ALK inhibitors have been pursued to overcome the drug resistance issues, resulting in development of ceritinib by Novartis and alectinib by Chugai. As our on-going search for ALK inhibitors, we have designed and synthesized derivatives of ceritinib to discover novel ALK inhibitors. Through numerous optimization processes, a pre-clinical candidate (KRCA-605) was discovered. KRCA-605 has a tetrahydroisoquinoline structure, distinct from the existing ALK inhibitors. Biologically, it has far more effective in mouse xenograft studies, compared with ceritinib. Moreover, while ceritinib is not active against G1202R mutant, a crucial crizotinib resistant mutant, KRCA-605 is quite active against G1202R, suggesting that it could circumvent the resistance issues. Activities and ADMETOx profiles of KRCA-605 will be presented.
II. Bruton’s tyrosine kinase (BTK) is a member of the Src-related Tec family cytoplasmic tyrosine kinases playing a crucial role in B cell malignancies. Ibrutinib (Imbruvica), an irreversible BTK inhibitor, was approved for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom's macroglobulinemia in 2013-2015, respectively. Although the efficacy of ibrutinib is formidable, the emergence of resistance predominantly from C481 mutations has been observed approximately 65% of CLL patients taking ibrutinib. Moreover, due to the ITK inhibition nature of ibrutinib, combitherapy with immune-checkpoint inhibitors is known to be ineffective. Under these circumstances, the discovery of second-generation BTK inhibitors circumventing resistance and immuno-combitherapy issues is in enormous demand. Thus, we have launched a BTK program to discover reversible BTK-non-ITK inhibitors. Compared with ibrutinib, one of our lead compounds exhibited more efficacious results in a murine xenograft model using TMD-8 cells. Current status of the discovery program will be discussed. |
| E-mail |
pkim@krict.re.kr |
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119th General Meeting of the KCS