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2022世界杯买球在线官网

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TGRX-678 BCR-ABL inhibitor

  • Novel mechanism
  • Best-in-Class potential
  • Global development rights
  • CDE clinical license obtained
  • First subject dosed
TGRX-678, an allosteric BCR-ABL1 inhibitor with a distinct mechanism of action and a novel structure, is used to treat patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph-CML) or CML patients with drug resistance mutations such as T315I. TGRX-678 is independently developed by the TargetRx R&D team and designed through the structure-based drug design method. TGRX-678 mimics the function of natural ABL1 myristoyl N-terminal polypeptide. TGRX-678 binds to the myristate site at the C-terminal of the kinase domain, causes the cross-linking of SH3 and SH2 domains to the kinase domain, thus effectively locking the kinase in its inactive state.

TGRX-678, belonging to Class 1 innovative drugs, has shown strong biological activity and excellent selectivity in preclinical studies is indicative of its top rank in China and commanding position internationally. Currently, Phase 1 clinical trial of TGRX-678 is ongoing at Peking University Institute of Hematology and has successfully conducted the dosing of the first human subject.

TGRX-678 is expected to overcome drug resistance to existing therapies as well as the drug intolerance issue and side effects problems. Besides, it is intended to break the plight of CML patients requiring life-long medication, and significantly improves the quality of life and prognosis of CML patients. Furthermore, the drug combination of TGRX-678 with the previous three generations of traditional inhibitors binding to catalytic sites provides enhanced synergistic effects aiming at dose reduction, toxicity relief, and efficacy improvement. Additionally, compared to single-drug therapy, combination therapy could effectively overcome drug resistance caused by multiple mutations. Thus, TGRX-678 provides a promising treatment option for CML patients to achieve treatment-free remission (TFR).

TGRX-326 ALK/ROS1 inhibitor

  • Next-generation ALK/ROS1 dual inhibitor
  • Powerfully Combating existing drug resistance
  • Global development rights
  • CDE clinical license obtained
    TGRX-326, a dual inhibitor of the ALK (anaplastic lymphoma kinase) and ROS1 (c-ROS proto-oncogene 1) receptor tyrosine kinases (RTKs), is the next-generation Class 1 innovative drug for the treatment of ALK/ROS1-positive non-small cell lung cancer (NSCLC). TGRX-326 was designed and optimized through data mining and molecular simulation approaches based on lead compounds which exerted strong inhibitory effects on ALK G1202R and ROS1 G2032R. Not only does TGRX-326 exert strong efficacy (especially towards ALK G1202R& ROS1 G2032R), high selectivity, excellent safety and tolerance concerning its in-vivo and in-vitro bioactivity profiles, but it possesses the potential to reduce clinical dose, reduce toxic side effects, improve drug tolerance and overcome drug resistance issues.

    The results of big data analysis and molecular simulations reveal that the conformational change of the ATP-binding glycine-rich loop (ALK G1202R and ROS1 G2032) was primarily responsible for the 1st and 2nd generation-ALK inhibitors resistance. Specifically, the resistance mechanism could be driven by steric effects when glycine at the ALK solvent front mutates into a positively charged arginine with extended side-chain amino acids. Consequently, the solvent front mutation was assumed to hinder drug binding. TGRX-326 with the novel molecular structure exerts the strong binding affinity for ALK G1202R and ROS1 G2032R, indicating an increasing potential to overcome the resistance of the G1202R/G2032R solvent front mutation.

    The development status of TGRX-326 stood at a leading position both domestically and internationally. Preclinical in-vivo and in-vitro studies have shown that TGRX 326 exert strong bioactivity and high selectivity for ALK G1202R and ROS1 G2032R. Currently, TGRX-326 is in a Phase 1 study for the treatment of non-small cell lung cancer at the Sun Yat-sen University Cancer Center (SYSUCC) and has completed the first subject dosing (FIH).

    The novel molecule structure properties of TGRX-326 show excellent bioactivity and high selectivity against ALK/ROS mutation-resistant NSCLC. Furthermore, TGRX-326 can cross the blood-brain barrier, indicating the significant potential for NSCLC patients with brain metastases. In addition, we are conducting extended indications for TGRX-326 with the purpose to maximize its medical value. Our goal is to provide patients in China with access to affordable drugs that are superior to the current standard of treatment.

    TGRX-814 BCL2 inhibitor

    • Best-in-Class potential
    • Overcoming drug resistance to existing cancer therapies
    • Global development rights
    • Broad clinical applications
    TGRX-814 is a highly selective inhibitor of the BCL2 (over BCL-XL) for the treatment of CLL with or without the del(17p)/TP53 mutation, NHL, SLL, DLBL, MM, etc. Notably, TGRX-814 has an excellent selectivity profile for BCL-XL. TGRX-814 is modified and optimized through classical bioisosterism and molecule simulation technologies. In-vitro and in-vivo assays have shown that TGRX-814 improves oral metabolism, increases in vivo exposure, and reduces compound clearance while maintaining in vitro and in vivo bioactivity. Moreover, TGRX-814 obtained over 2-fold increase in bioavailability compared to the marketed drug Venetoclax, resulting in a significant increase in efficacy.

    Currently, TGRX-814 is in the IND-enabling phase and would soon enter the clinical phase, offering patients better treatment options and hope of prolonged survival.

    TGRX-072 ALK/EGFR inhibitor

    • Best-in-Class potential
    • Overcoming drug resistance to existing cancer therapies
    • Targeting L1196M mutation
    • Global development rights
    TGRX-072, a 2nd-generation ALK and 4th-generation EGFR dual-target inhibitor novel Class 1drug, is used for the treatment of metastatic NSCLC that is resistant or intolerant to the 1st-generation ALK inhibitor crizotinib, especially for the ALK L1196M mutation. TGRX-072 could cross the blood-brain barrier, resulting in potential efficacy in ALK-positive NSCLC patients with brain metastases. Additionally, TGRX-072 represents a novel selective inhibitor that can overcome T790M/C797S-mediated resistance. TGRX-072 is designed through rational drug design approach, inducing specific pharmacophore which results in high selectivity, low off-target toxicity and high metabolic stability.

    According to the clinical and safety data of its competitors, TGRX-072 is presumed to have significant advantages over erlotinib and ceritinib. Additionally, its excellent blood-brain barrier permeability indicates its potential efficacy against ALK-positive NSCLC with brain metastases. As the 4th-generation EGFR inhibitor, TGRX-072 brings a ray of hope to patients with acquired T790M/C797S-mediated resistance to the 3rd-generation inhibitors. Currently, TGRX-072 is actively preparing for the clinical trial application.

    TGRX-360 EGFR inhibitor

    • Best-in-Class potential
    • Overcoming drug resistance to existing cancer therapies
    • Targeting L858R/T790M mutation
    • Global development rights
    TGRX-360, a Class 1 new drug independently developed by TargetRx, is a 3rd-generation inhibitor targeting EGFR T790M mutation in NSCLC, a common cause of acquired resistance to 1st- and 2nd-generation EGFR TKIs. The mutant-selective TGRX-360, with the potential to overcome resistance to existing therapies, is designed and optimized through the fragment-based drug design and the covalent binding energy calculation approaches.

    Preclinical studies have indicated that TGRX-360 is 4-fold more active against L858R/T790M mutant EGFR enzymes and inhibits the proliferation of H1975 cell line (EGFR L858R/T790M mutation) about 5-10 fold stronger than osimertinib. Additionally, TGRX-360 exhibits 8.96-fold higher selectivity for EGFR L858R/T790M against EGFR WT, which is 4-fold higher than osimertinib. TGRX-360 exhibits excellent absorption performance in rats after oral administration, achieving 1.7-fold bioavailability compared with osimertinib. In conclusion, TGRX-360 has shown better activity, selectivity and bioavailability than the 3rd-generation EGFR inhibitor osimertinib, indicating its best-in-class potential among 3rd-generation EGFR TKIs. Furthermore, its first-line-medication potential could provide patients with better treatment options and improve quality of life and survival in patients with cancers. Currently, TGRX-360 is in the preparation process for the clinical trial application.
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