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PARP 및 Tankyrase를 동시에 억제하는 신규 항암 기전을 갖는 세계 최고 수준의 비임상 후보물질을 도출
• SBDD 및 QSAR을 이용하여 PARP 및 Tankyrase를 동시에 억제하는 신규 저해제 디자인함.
•...

PARP 및 Tankyrase를 동시에 억제하는 신규 항암 기전을 갖는 세계 최고 수준의 비임상 후보물질을 도출
• SBDD 및 QSAR을 이용하여 PARP 및 Tankyrase를 동시에 억제하는 신규 저해제 디자인함.
• 신규 화합물 합성 및 in vitro 효능 평가함.
• 종양 세포주에서 in vitro 및 in vivo tumor xenograft 모델에서의 효능 실험 실시함.
• PK, Non-GLP 안전성 약리시험, Non-GLP 일반 독성시험 및 Off-Target profiling 등을 수행하여 비임상 후보물질 도출함 (JPI-547)
• Sale-up process 개발 및 비임상 연구용 원료 합성 연구 완료함.
• 비임상 후보물질의 pre-formulation 연구 완료함.
• 비임상 원료 합성 및 비임상 후보물질의 안정성 시험 완료함.
• 국내 물질특허 출원을 완료함
• JPI-547은 항암신약개발사업단과 환자 맞춤형 신규 대장암 치료제로 공동개발계약을 체결하고 연구를 수행 중에 있음.

( 출처 : 요약서 3p )

Abstract
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Colorectal cancer (CRC) is the second leading cause of mortality among cancer patients in the world and is the third most diagnose...

Colorectal cancer (CRC) is the second leading cause of mortality among cancer patients in the world and is the third most diagnosed cancer globally, and thus represents a huge burden on healthcare systems. Olaparib, the first PARP inhibitor, has recently been approved for treating ovarian cancers with BRCA1/2 mutations. Olaparib has also shown promising clinical progress in metastatic prostatic cancers. However, PARP inhibitors include olaparib have not shown sufficient efficacy to colorectal cancer cell lines. The demonstration in 2009 that tankyrase inhibitors can restrict Wnt signalling and inhibit colorectal tumour cells has proved to be one of the more promising findings in this area. However, tankyrase inhibitors have not shown sufficient efficacy in vivo animal models.

We have discovered the PARP/tankyrase (TNKS) dual inhibitor to show synergistic effect against several cancer cells. The PARP/TNKS dual inhibitor, JPI-547 shows good in vitro and in vivo efficacy, excellent pharmacokinetic and safety profile. We are conducting preclinical study for the first in class colorectal cancer drug with a predictive new biomarker with National OncoVenture. We also have planned to expand indication of PARP/TNKS dual inhibitors to several cancers such as ovarian, prostate, breast, and blood cancers. There is a robust patent portfolio protecting the lead series with both composition of matter and medical use claims to the key compounds.

Our PARP/TNKS dual inhibitor has exhibited low nanomolar potency against PARP and tankyrase with the following characteristics:
Potency
Low nM activity against PARP in cell-free and cell-based assays.
Low nM activity against Tankyrase in cell-free assay
DMPK
Good solubility (> 1.0mM)
Optimal lipophilicity (clogP~2.3)
No P-gp substrate
Good oral bioavailability ( %F~70%) with long plasma half-life (>3h) in vivo (mouse)
Safety and toxicity
No animal death at 2000mpk in single tox (mouse)

( 출처 : SUMMARY 6p )

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