Page 84 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-49]

Discovery of the first potent proteolysis targeting chimera

(PROTAC) degrader of AIMP2-DX2 as a lung cancer drug

BoRa LEE¹, Dae Kyu KIM²˙#, Aram LEE¹, Young Mi KIM¹, Lianji CUI¹, Sunghoon KIM²˙*, Inhee CHOI¹˙*

¹Medicinal Chemistry, Institut Pasteur Korea, Seongnam-si 13488, Rep. of Korea, ²Medicinal Bioconvergence

Research center, College of Pharmacy and College of Medicine, Gangnam Severance hospital, Yonsei University,
Incheon 21983, Rep. of Korea

Proteolysis targeting chimera (PROTAC) technology have attracted great attention in drug discovery and

development areas A splicing variant of AIMP2, AIMP2-DX2 (DX2), is highly expressed in lung cancer cells and lung

cancer patient tissues. To date, many attempts have been made to develop DX2 inhibitors but due to the lack of
satisfactory activity against DX2, new therapeutic strategies are needed to develop a novel drug for DX2. It is already
reported that DX2 selectively binds to 70 kDa heat shock proteins (HSP70s) but HSP70s inhibit ubiquitination

mediated degradation of DX2 and Siah1, a specific E3 ligase of DX2. Therefore, to target DX2, specific compounds
are required to interrupt the interaction between DX2 and HSP70. Here we designed and synthesized DX2 PROTACs

using the most potent hit compound BC-DXI-495 as the targeting protein ligase ligand, and CRBN (pomalidomide
and thalidomide) as the Siah1 E3 ligase ligand based on the binding assay. Linker length of PROTACs were

optimized based on inhibitory activities measured by the luciferase assay. Consequently, our data confirmed the
applicability of PROTAC technology to target DX2 and proved DX2 PROTAC compounds could potentially lead to

therapeutic opportunities to treatment of lung cancer.