KRAS reducer suppresses pancreatic cancer malignancy
KRAS 減速器抑制胰腺癌惡性腫瘤
SW1 is an ADAM9 inhibitor that can promote KRAS protein degradation and enhances the efficacy of gemcitabine in pancreatic cancer treatmen
SW1 是一種 ADAM9 抑製劑，可促進 KRAS 蛋白降解，增強吉西他濱治療胰腺癌的療效
Targeted indication
Pancreatic ductal adenocarcinoma
Status
Pre-clinical studies
Key features
- • High anti-KRAS activity efficacy
- • Small compound with a stable pharmacokinetic profile
- • Favorable safety profile with no side effects
Market
Use of anti-KRAS therapy, including reducing KRAS protein and activity in pancreatic cancer treatment. Importantly, SW1 with a very high safety profile can potentially synergize with clinical-used gemcitabine to block KRAS signaling in KRAS wild-type and mutants. Furthermore, SW1 exhibits a stable pharmacokinetic profile in preclinical studies.
MODE OF ACTION
Current understandings of ADAM9 function in tumorigenesis are (1) inducing NK-related immune evasion, (2) increasing extrinsic RTK signals, and (3) stabilizing all KRASwt/mt proteins. SW1, a novel selective ADAM9 inhibitor, blocks ADAM9 activity and reduces its protein amount which has the benefits to disrupt known regulation mechanisms of tumorigenesis. Moreover, SW1 enhances the chemosensitivity in vivo models
EXPERIMENTAL RESULTS
• SW1 is a specific ADAM9 inhibitor targeting its protease function and reducing its protein amounts
• SW1 broadly reduces KRAS proteins in KRAS wild-type and mutants
• A combination of SW1 and gemcitabine shows potent anti-cancer effects
• SW1 suppresses tumor growth and prolongs survival in the KrasG12D spontaneous pancreatic cancer model
• The combination of SW1 and gemcitabine suppresses tumor growth and prolongs survival in the syngeneic pancreatic cancer model
• Potent efficacy of the combination of SW1 and gemcitabine in the patient-derived cell xenograft model (CR:70%; PR:20%; SD: 10%)
• Mice are tolerant in the 2-month daily treatment of SW1 without any blood cell count change or liver/kidney damage
• SW1 is very stable on the physical and chemical properties at 4 weeks under acceleration conditions
INTELLECTUAL PROPERTY
SELECTED PUBLICATIONS
Theranostics 11(8):3661-3675. January 26, 2021
Cancer Research 74(18):5229-43. September 2014
BUSINESS OPPORTUNITY
License and/or Collaboration and Sponsored Research
CONTACT
service@biip-dcc.org