<p>Supplementary Information: provides experimental procedures in details, as well as two tables and one figure. Table S1. Features and relative expression levels of MPHOSPH1 of clinical samples. Table S2. Hepatic function assays of the orthotopic HCC xenograft animal model. Figure S1. In vivo knockdown of endogenous MPHOSPH1 inhibits orthotopic HCC xenograft growth. Tumor nodules are indicated with yellow arrows.</p>
Abstract Proto-oncoprotein RET (rearranged during transfection) is a receptor tyrosine kinase and belongs to the cadherin superfamily. RET fusion proteins and gatekeeper mutations represent strong cancer drivers involved in the development of a variety of cancers. Although selective RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU667) were recently marketed for patients with RET-dependent NSCLC and thyroid cancers, RET solvent front mutations G810R/S/C/V and other secondary mutations such as Y806C/N and V728A have been identified as mechanisms counting for acquired resistance to the two drugs and limits the applications of the kinase inhibitors. To provide novel RET inhibitors effective to a broader spectrum of RET fusions and mutations, we identified TY-1091 as a novel next-generation RET inhibitor through the in-house RET program and systemic screening of RET compound candidates. TY-1091 was characterized for its anti-tumor activity through in vitro and in vivo testing of a variety of RET-dependent tumor models including a panel of 17 engineered RET mutant Ba/F3 cell lines and 2 cancer cell models. The results show that TY-1091 inhibits wild type and major RET mutants (IC50, nM): RET G810S (9.5 nM), RET V804M/L/E (2.8-12.6 nM), and double mutants RET V804M/G810S (23.5 nM) and M918T/G810S (47.0 nM) through a biochemical screening against a panel of 17 engineered RET mutant Ba/F3 cell lines. Importantly, the inhibitory activity of TY-1091 is much higher than that of first-generation RET inhibitor Cabozantinib, and comparable to other second-generation compounds LOXO-292 and BLU-667. Consistent with its mode of action, TY-1091 grants extraordinary inhibition effects to tumor cell proliferation compared to its peer compounds LOXO-292 and BLU-667 (including TT (thyroid cancer, RET C634W) and LC2/ad (NSCLC, CCDC6-RET)), and the inhibition of the RET pathway activation, i.e., inhibition of RET phosphorylation (IC50 < 1 nM), SHC phosphorylation (IC50 = 4.6 nM) and ERK phosphorylation (IC50 = 9.8 nM) in Ba/F3-KIF5B-RET cells further validated the above in vitro phenotype. The therapeutic potential of TY-1091 was then further validated through mouse pharmacology in that TY-1091 demonstrated remarkable anti-tumor efficacy in a variety of xenograft models including Ba/F3 KIF5B-RET (wt), Ba/F3 KIF5B-RET (V804L), TT (thyroid cancer, RET C634W), and LC2/ad (NSCLC, CCDC6-RET). Detailed data will be presented. In summary, TY-1091 is a highly potent, orally available, and safe small molecule inhibitor to pan-RET mutations in cancer, and may attenuate SFMs-mediated resistance to existing RET therapy. The IND clearance from the US FDA was received and Phase I clinical investigations of TY-1091 shall be launched in the US soon. *To Whom Correspondence should be addressed to: Jun Li, Chengshan Niu and Yusheng Wu Citation Format: Chengshan Niu, Maolin Zheng, Huan Wang, Kaige Ji, Meihua Li, Guohui Wang, Rongzhen Ni, Apeng Liang, Aishen Gong, Yazhen Zhang, Hui Su, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Jun Li, Yusheng Wu. TY-1091, a highly selective and potent second-generation RET inhibitor, demonstrates superior antitumor activity in multiple RET-mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3419.
Abstract Epidermal growth factor receptor (EGFR) activating mutations represent major drivers to the development of non-small cell lung cancer (NSCLC). Among the oncogenic EGFR mutations, a significant cohort, counting for approximately 4-10% of the EGFR mutation spectrum, bear EGFR exon 20ins mutations. Meanwhile, approximately 2% of NSCLC patients bear hotspot mutations in HER2. Strikingly, over 90% of the HER2 mutations occurred in NSCLC are identified as exon 20ins mutations. Despite the successful launch of 1st, 2nd, and 3rd generation of EGFR inhibitory agents in the clinic that inactivate oncogenic EGFR signaling through targeting specific EGFR mutations, de novo or acquired, none of these standard-of-care therapies is specific to EGFR exon 20ins or HER2 exon 20ins. In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation. Considering the large population of lung cancer and the fact that many patients are missed in diagnosis due to the heterogeneous characteristics of EGFR and Her2 exon 20ins, there are probably more than ten thousand lung cancer patients suffering the EGFR or Her2 exon 20ins mutations. There are urgent unmet medical needs to develop target therapeutics for EGFR and Her2 exon 20ins mutations. We discovered and developed TY-4028, which is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon 20ins mutations and is currently in the IND enabling stage. In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008. The B/P ratio (brain tissue AUC0-last/plasma AUC0-last) of SD rats was 1.63 and 1.04 respectively after oral administration of TY-4028 in male and female SD rats, which suggested that TY-4028 had good potential to cross Blood Brain Barrier (BBB). Preclinical studies showed a good PK profile and manageable toxicity with TY-4028. TY-4028 has remarkable efficacy in mouse models of EGFR exon 20ins and HER2 exon 20ins. The data showed that all doses of TY-4028 had significant effects, and the tumors nearly demonstrated complete regression in the PDX LU0387 model and PC9 CDX model. At the same dose, the efficacy of TY-4028 was similar to that of TAK-788, while the tolerance of TY-4028 was better than that of TAK-788. At the same dose, the efficacy of TY-4028 was better than that of DZD9008. Taken together, the data demonstrated TY-4028 has great potential to meet the unmet medical needs for NSCLC patients with EGFR exon 20ins mutation or HER2 exon 20ins mutation. #Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors. Citation Format: Jun Li, Chengshan Niu, Zhongwei Guo, Huan Wang, Bailu Zheng, Yuge Dou, Apeng Liang, Kaige Ji, Shengli Dong, Meihua Li, Yanchao Zhao, Yazhen Zhang, Aishen Gong, Hao Liu, Xinmiao Hu, Hui Su, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Yusheng Wu. TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4488.
MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC.
Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (Cmax ) compared with the osimertinib in rats and human body.
<p>Supplementary Information: provides experimental procedures in details, as well as two tables and one figure. Table S1. Features and relative expression levels of MPHOSPH1 of clinical samples. Table S2. Hepatic function assays of the orthotopic HCC xenograft animal model. Figure S1. In vivo knockdown of endogenous MPHOSPH1 inhibits orthotopic HCC xenograft growth. Tumor nodules are indicated with yellow arrows.</p>
Abstract Although tyrosine kinase inhibitors (TKIs) with activity against ALK, ROS1, or TRKA-C have significantly improved clinical benefits in patients with diverse tumors harboring ALK, ROS1, or NTRKs rearrangements, drug resistance will be developed and subsequent therapy overcoming acquired resistance remains limited. The resistance is mainly caused by the adaptive mutations evolved in the structural region of ROS1/TRK/ALK kinases, especially solvent front substitutions such as ROS1 G2032R/TRKA G595R/ALK G1202R mutations. Next-generation TKIs targeting these mutations could potentially address this unmet medical need. Currently, several inhibitors, including TPX-0005, are under development in phase I/II clinical trials. Here, we report the finding of a novel small molecule, TY-2136b, which has been identified through a systemic approach against acquired ROS1/TRK/ALK mutations. Kinase assay results suggest that TY-2136b grants similar potency to TPX-0005 inhibiting ROS1 G2032R mutant activity (IC50 1.6 nM vs 2.4 nM ), confers significantly stronger potency than LOXO-101 inhibiting TRKA activity with G595R substitution (IC50 0.8 mM vs 460.1 nM ). The cell proliferation assay results with Ba/F3 cells suggest that TY-2136b is similar potent as TPX-0005 inhibiting cell proliferation of the Ba/F3 strain expressing mutant ROS1 bearing G2032R mutation, a major resistance mutation. TY-2136b also shows potent inhibition towards ROS1, ERK and AKT phosphorylation and downstream signaling in Ba/F3-CD74-ROS1-G2032R cells. Meanwhile, TY-2136b, TPX-0005, and TRK-selective second-generation LOXO-195 inhibitors had similar activity against TRKA G595R and TRKC G623R resistance mutations, but TY-2136b was better than TPX-0005 and LOXO-195 against TRKA G595R/F589L dual mutations in vitro. In vivo studies, TY-2136b showed dose-dependent anti-tumor effect at the dose of 5, 10, and 20 mg/kg, bid, in xenograft tumor models carrying ROS1 G2032R and TRKA G595R mutation, and was more effective than Crizotinib and LOXO-101 at testing dose, and showed better efficacy than TPX-0005 in higher dose. Next, in vivo activity of TY-2136b was examined with xenograft model of KM-12 expressing TPM3-NTRK1 fusion proteins. The results show that TY-2136b and TPX-0005 demonstrate more effectiveness than LOXO-195, and the animals tolerated TY-2136b better than TPX-0005. In the ALK-G1202R xenograft model, TY-2136b showed a significant anti-tumor effect in a certain dose-dependent manner. Taken together, our preclinical data demonstrate that TY-2136b can treat cancers caused by ROS1/TRK/ALK mutations and overcome drug resistance due to acquired solvent-front mutations. Currently, TY-2136b is under first-in-human clinical investigations in the US and China. * To Whom Correspondence should be addressed to: Jun Li, Chengshan Niu and Yusheng Wu Citation Format: Chengshan Niu, Apeng Liang, Yuge Dou, Kaige Ji, Meihua Li, Yanchao Zhao, Yan Zhang, Zhongwei Guo, Aishen Gong, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Jun Li, Yusheng Wu. TY-2136b, a next generation ROS1/TRK/ALK inhibitor, potently inhibits kinase and cell proliferation activities of tumor cells bearing drug-dependent acquired mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3400.
Abstract：Glucagon-like peptide-1 (GLP-1), which has been extensively applied for treating type 2 diabetes mellitus (T2DM), is an incretin hormone that regulates glucose homeostasis.GLP-1(28-36)amide, a C-terminal nonapeptide (FIAWLVKGRamide) of GLP-1, is a major product derived from the cleavage of GLP-1 by the neutral endopeptidase (NEP).GLP-1(28-36)amide has long been regarded as a metabolically inactive byproduct, however, recent findings reveal that GLP-1(28-36)amide plays multiple novel roles in ameliorating hepatic metabolism, protecting β cells, improving glucose disposal and inhibiting weight gain.Here, we summarize the latest progress on the effects of GLP-1(28-36)amide with a focus on its roles in regulating the Wnt and mitochondrial-mediated signaling pathways.
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