Abstract 1286: AGX87 - An IND-stage potent and selective next-generation NTRK/ROS1 inhibitor of WT and clinical resistant mutants with superiority over tyrosine kinase inhibitors currently approved or in development

作者: Lee, Francis Y.F. ; Yang, Zhiqiang ; Tan, John Q. ; Wu, Wen-Lian

AbstractAGX87 - An IND-stage potent and selective next-generation NTRK/ROS1 inhibitor of WT and clinical resistant mutants with superiority over tyrosine kinase inhibitors currently approved or in developmentBackground: Fusions of the neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1,2,3; and the ROS proto-oncogene 1 receptor tyrosine kinase gene (ROS1) are key driver mutations in several solid malignancies, including non-small cell lung cancers. While the 1st generation TKIs larotrectinib (LOXO101, LAR), entrectinib (ENT) and crizotinib (CRI) have provided effective initial treatment for patients with cancers harboring these mutations, acquired resistance including secondary kinase domain mutations invariably arise.Methods: Kinase and cell proliferation inhibition and in vivo antitumor activity were determined using recombinant kinases and engineered NIH3T3 or Ba/F3 cells expressing WT or mutated TRKs and ROS1, respectively. Results: Superior efficacy of AGX87 was demonstrated in a series of NTRK and ROS1 tumor models. While both 1st and next generation inhibitors were effective against tumors with WT fusion mutations, AGX87 was the only compound that has significant in vivo efficacy in tumors that harbor the G667C TRKA or the ROS1 G2032R mutations; in both cases yielding antitumor activity greater than 1 log cell kill (LCK). In kinase assay, AGX87 was >10-fold more potent (IC50=0.5 nM) than LAR and ENT, and 6-fold more potent than LOX195 in WT TRKA. Against the resistant solvent-front (G595R) mutant AGX87 was >1000-fold more potent (IC50=0.2 nM) than LAR and ENT and 20-fold more potent than LOXO195. Against the glycine DFG (G667C) mutant, AGX87 was >20-fold more potent (IC50=8.5 nM) than all three TKIs. In cells, AGX87 was >30-fold more potent (IC50=0.7 nM) than LAR and ENT vs. WT TRKA and >30-fold more potent (IC50=29 nM) vs. the G667C mutant. Comparing with LOXO195, AGX87 was 8 and 4-fold more potent vs. the WT and G667C mutant, respectively. Against WT ROS1 and G2032R, the most important solvent-front mutation found in pretreated patients, AGX87 has IC50s of 0.3 and 0.7 nM, respectively. In contrast, ENT and CRI have similar IC50s in WT kinase, but were 42 and 58-folds less potent vs. the mutant kinase. In cell assay, AGX87 has comparable IC50 as ENT and CRI but was 100 and 20-fold more active in BAF/3 cells that harbor the resistant G2032R mutation. In nonclinical ADME studies, AGX87 has good bioavailability (F≥50% in mouse, rat and dog), acceptable metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction).Conclusion: AGX87 demonstrated best-in-class activity against WT and mutated TRKs and ROS1 and exhibited excellent drug-like properties. IND enabling studies are in progress.Citation Format: Francis Y.F. Lee, Wen-Lian Wu, Zhiqiang Yang, John Q. Tan. AGX87 - An IND-stage potent and selective next-generation NTRK/ROS1 inhibitor of WT and clinical resistant mutants with superiority over tyrosine kinase inhibitors currently approved or in development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1286.

2021-07-01·Cancer Research

Abstract 1145: AGX323 - A SAM-competitive, orally available inhibitor of protein arginine methyltransferase 5 (PRMT5) with potent cellular antiproliferative and in vivo antitumor activity against selected solid cancer types

作者: Yang, Zhiqiang ; Tan, John ; Lee, Francis Y. F. ; Wu, Wen-Lian

AbstractBackground: Protein arginine methyltransferase 5 (PRMT5) is an attractive therapeutic target because of its involvement in key oncogenic mechanisms including epigenetics, DNA response and RNA processing. Early development of PRMT5 inhibitors has focused on hematological malignancies although more recently several compounds have entered the clinic for both liquid and solid malignancies. Early Phase I clinical data indicate dose-limiting hematological toxicity, particularly anemia and thrombocytopenia. We focused our effort in discovering compounds with potent inhibitory activity against cells from solid cancer types known to overexpress PRMT5 and which correlated with poor prognosis (NSCLC, breast, bladder and pancreatic cancers).Methods: Enzyme inhibition was conducted using a PRMT5:MEP50 flash plate assay, with S-adenosylmethionine (SAM) as the methyl donor and histone H4 as substrate. Inhibition of cell proliferation was assessed in various cancer lines using a 7-day cellTitre-Glo (CTG) assay. Binding mode of the inhibitors to PRMT5 was investigated using surface plasmon resonance (SPR). In vivo antitumor activity was evaluated in various human cancer models grown in immunocompromised mice.Results: Structure activity relationship of a series of over 50 close analogs demonstrated that in vitro anticancer activities correlate poorly with enzyme inhibition potency. To understand this discrepancy we used SPR to study the PRMT5 binding mode of cell active and inactive compounds in the presence of various endogenous substrates (SAM, SAH or MTA). We obtained binding affinity (KD), association constant (Ka) and dissociation constant (Kd) of exemplars of active and inactive inhibitors and correlated their relationship to cell activity. The lead compound AGX323 has a KD of 1.8 x 10-10 M to SAM-bound PRMT5 and exhibited potent antiproliferative activity against a panel of over 20 human solid epithelial cancer cell lines from lung, breast, bladder and pancreas, with nM potency. For example, in the H1048 human lung cancer model it has an enzyme inhibition IC50 of 0.8 nM, a cell proliferation IC50 of 1.7 nM and when given to tumor bearing mice it demonstrated robust antitumor activity at well-tolerated dose levels. In nonclinical ADME studies, AGX323 demonstrated favorable drug-like properties: including acceptable oral bioavailability (in mouse, dog and monkey) and systemic exposure following oral administration, excellent metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction).Conclusion: AGX323 demonstrated potentially best-in-class activity in PRMT5 dependent human solid cancer models and exhibited excellent drug-like properties. IND enabling studies are currently planned.Citation Format: Francis Y. F. Lee, Wen-Lian Wu, Zhiqiang Yang, John Tan. AGX323 - A SAM-competitive, orally available inhibitor of protein arginine methyltransferase 5 (PRMT5) with potent cellular antiproliferative and in vivo antitumor activity against selected solid cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1145.

2020-08-15·Cancer Research

Abstract 1942: AGX73 is an effective treatment for hepatocellular carcinoma (HCC) by selective inhibition of immunokinases that play crucial roles in the crosstalk between cancer and immune cells in the tumor microenvironment

作者: Lee, Francis Y.F. ; Yang, Zhiqiang ; Tan, John ; Wu, Wenlian

AbstractHCC is the second leading cause of cancer-related death and the fifth-most-common cancer worldwide. Unlike almost all other tumor types, the vast majority (90%) of HCCs develop due to underlying chronic inflammation, the induction of fibrosis and/or subsequent cirrhosis. In established disease, persistent upregulation of inflammatory signals in the tumor microenvironment leads to suppression of antitumor immune response by various mechanisms such as reprogramming of tumor-associated macrophages (TAMs) and loss of critical immune cell subsets (e.g. tumor-infiltrating lymphocytes). We identified 6 key immunokinases (AXL, DDR1, DDR2, FMS, KIT and MER) that are frequently amplified in HCC and are significant predictive markers of poor outcome (TCGA). We design small molecule compounds that potently and selectively inhibit these kinases. AGX73, optimized for drug-like properties, is an orally bioavailable compound currently undergoing IND evaluation as potential clinical candidate for first-in-human trial. In in vitro assay, carried out at high ATP concentration (100 μM), AGX73 inhibited the activity of recombinant human AXL, DDR1, DDR2, FMS, KIT and MER with IC50 values of 30, 12, 0.63, 96, 54, and 40 nM, respectively, but was highly selective against a panel of 374 kinases. In an in vitro primary macrophage assays, AGX73 promoted M1 macrophage polarization and increased the secretion of IL-6 and TNFα. In contrast, AGX73 suppressed the activation of M2 macrophages and decreased the secretion of IL-10. Importantly, AGX73 prevented the reprogramming of human LPS/IFN-γ polarized M1 macrophages back to M2 macrophages. In contrast, AGX73 had no effect on the reprogramming of IL-4/IL-13 polarized M2 macrophages back to M1. In vivo, in the MC38 colon carcinoma model, AGX73 treatment reduced the number of TAMs, from 46 to 22% of the total CD45+ cells in the tumors. Moreover, the M1/M2 ratio was favorably increased, from 1.3 to 1.8. AGX73 demonstrated robust antitumor activity in multiple (11) patient-derived xenograft (PDX) models of HCC, with tumor growth inhibition (TGI) ranging 62-105% (Median = 84%) and was effective at multiple dose levels, from 30-150 mg/kg. In combination with anti-PD1 (10 mg/kg) in the MC38 model, AGX73 produced synergistic activity at multiple dose levels. In nonclinical ADME studies, AGX73 demonstrated favorable drug-like properties: including good bioavailability (F>50% in mouse, rat and monkey) and systemic exposure following oral administration in multiple species, acceptable metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction) and excellent cardiac safety profile. IND toxicologic studies are currently in progress.Citation Format: Francis Y.F. Lee, Wenlian Wu, Zhiqiang Yang, John Tan. AGX73 is an effective treatment for hepatocellular carcinoma (HCC) by selective inhibition of immunokinases that play crucial roles in the crosstalk between cancer and immune cells in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1942.

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药物(靶点)	适应症	全球最高研发状态

immunokinase inhibitor(Angex Pharmaceutical)	肝癌更多	临床申请批准
mTOR inhibitor(Angex) ( mTORC1 x mTORC2 )	实体瘤更多	临床前
AGX-323 ( PRMT5 )	实体瘤更多	无进展
AGX-73 ( AXL x CSF-1R x DDR1 x DDR2 x MerTK x c-Kit )	肝细胞癌更多	无进展
AGX-87 ( NTRK x ROS1 )	实体瘤更多	无进展