ABOUT
PROTAC technology has a unique mechanism
1.The PROTAC molecule specifically recognizes and binds to the target protein through the target protein ligand (POI Ligand) at one end and the E3 Ligase through the E3 Ubiquitin Ligase Ligand (E3 Ligase Ligand) at the other end.
2.Forming the POI-PROTAC-E3 Ligase Ternary Complex.
3. In this ternary complex, the target protein POI is ubiquitinated by E3 ligase, and the ubiquitinated POI is subsequently recognized and degraded by the proteasome, thereby eliminating the target proteins.
Advantages of PROTAC Technology in Drug Development- Broaden the Range of Druggable Targets（undruggable）The molecular mechanism of PROTAC is to eliminate the target protein through the ubiquitin-proteasome system. This mechanism does not need a specific region on targets for drugs to bind like the traditional inhibitors do which functions through competitive binding. This makes some “non-druggable” target proteins “druggable”.
- High EfficiencyPROTAC molecules eliminates the target protein to amino acids through the ubiquitin-proteasome system and then can be released to react with other targets. Therefore PROTAC has the characteristics of recyclability, low dosage and high efficiency.
- Non-ImmunogenicCompared with biotechnology drugs, PROTAC does not trigger the production of anti-drug antibodies.In conclusion, PROTAC has become a hotspot in the field of drug research and development which has been paid great attention by scientific research institutions and pharmaceutical companies worldwide.
Introduction of Medicilon PROTAC Services- Design and Synthesis of Target Protein PROTAC-POIMedicilon gathers the popular POI ligands and multiple tissue types of E3 ligase ligands, in addition of established a linker library containing hundreds of linking molecules.Moreover, Medicilon’s CADD technology platform has greatly improved the quality of PROTAC-POI design and synthesis.
- In Vitro Screening of PROTAC-POICytotoxicity Assay (CCK-8 & CTG)Mechanism detection by proliferation inhibition tests.
Percentage degradation of HiBiT-IRAK4 in HiBiT-IRAK4 overexpression OCI-LY10 cells
Western Blot（WB）Conduct WB to test target protein degradation ability and analyze DC50.
Western blot of anti-IRAK4 on OCI-LY10 cells treated with IRAK4 degrader-1
Pomalidomide (CRBN binder) competition experiment show that IRAK4 degrader-1 degrades IRAK4 through CRBN
MG132 inhibition experiment show that IRAK4 degrader-1 degrades IRAK4 through proteasome pathway
Tumor cell proliferation inhibition effect test
Growth inhibition effect of IRAK4 degrader-1 on OCI-LY10 cells
ACBI1 (BRM degrader) degrades BRM in dose response manner
- In Vivo Efficacy Tests of PROTAC-POICDX Mouse Tumor Model
Cancer Type Orthotopic Model Orthotopic Model (Luc Cell Line) Brain Cancer U87-MG U87-MG-luc Lung Cancer NCI-H1650, A549, NCI-H1975, NCI-H460, LLC1 A549-luc, LLC1-luc,NCI-H1975-luc Colon Cancer HCT-116, LoVo HT29-luc Gastric Cancer Hs 746T Pancreas Cancer Mia-Paca 2 Mia-Paca 2-luc Breast Cancer MDA-MB-231 4T1-luc Ovarian Caner SK-OV-3 SK-OV-3-luc Prostate Cancer PC3 PC-3-luc Renal Cancer A498 Bladder Cancer UM-UC-3 Melanoma B16-F10-luc Liver Cancer H22 Bone Cancer PDX Mouse Tumor ModelCancer Type Cell Lines Colon Cancer PDXM-008C, PDXM-016C, PDXM-020C, PDXM-021C, PDXM-057C, PDXM-060C, PDXM-075C, PDXM-076C, PDXM-087C, PDXM-104C, PDXM-095C, PDXM-084C, PDXM-072C, PDXM-069C, PDXM-057C, PDXM-015C, PDXM-002C, Lung Cancer PDXM-054Lu, PDXM-050Lu, PDXM-047Lu, PDXM-053Lu, PDXM-028Lu, Gastric Cancer PDXM-092Ga, PDXM-091Ga, Breast Cancer PDXM-201B, PDXM-202B, PDX-203B Liver Cancer PDXM-211Li, PDXM-212Li Pancreas Cancer PDXM-221Pa, PDXM-222Pa Bladder Cancer PDXM-231U, PDXM-232U Lymphoma PDXM-241Ly, PDXM-242Ly - Integrated Preclinical ServicesWe can further proceed the R&D of the potential PROTAC molecule by facilitating our integrated preclinical services including CMC services, DMPK studies, safety evaluation, etc.The pharmacokinetics (PK) data show that five highly potent androgen receptor (AR) degraders achieve good to excellent overall PK profiles with ARD-2128 being the best compound. ARD-2128 has low clearance (1.2 mL/min/kg) and a moderate to high steady-state volume of distribution (Vss) of 2.7 L/kg. ARD-2128 (2 mg/kg, i.v.) and ARD-2128 (5 mg/kg, p.o.) both have long half-lives following intravenous and oral administration with the T1/2s of 27.6 h and 18.8 h, respectively. ARD-2128 (5 mg/kg) achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity.
Summary of PK Data for Five Compounds in Male ICR Mice[1]The plasma and microsomal stability data show that ARD-2128 has excellent plasma and microsomal stability in in mouse, rat, dog, monkey, and humans.
Evaluation of ARD-2128 for Its Plasma Stability and Microsomal Stability[1]References:[1].Xin Han,et al. Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer.J Med Chem. 2021 Sep9;64(17):12831-12854. doi: 10.1021/acs.jmedchem.1c00882. Epub 2021 Aug 25