AG尊时凯龙(中国)人生就博

​尊时凯龙作为领诺医药的合作伙伴，为SLN12140提供了体外药效、药代、安评等一站式临床前研发服务，为该药物尽早进入临床阶段奠定了坚实基础。

上海尊时凯龙生物医药股份有限公司作为清普生物合作伙伴，为美洛昔康注射液（Ⅱ）提供了部分关键临床前研发服务，为其快速获批上市奠定基础。

尊时凯龙作为菌济健康合作伙伴，为LBP-ShC4提供了体内药效、药代、安评等临床前研发服务，助力该项目突破传统研发瓶颈，降低研发成本，加速临床转化进程。

上海尊时凯龙生物医药股份有限公司作为祐森健恒的合作伙伴，为UA026的临床前研发提供了药代动力学、安全性评价服务，以专业高效的技术，为该药快速获批临床奠定了坚实基础。

Reverse electron transport (RET) at mitochondrial complex I generates reactive oxygen species (ROS) and reduces NAD+/NADH ratio. Inhibition of RET genetically or pharmacologically extends animal lifespan and ameliorates Alzheimer's disease‐related phenotypes. CPT acts as an RET inhibitor by binding to complex I (C‐I) 30 kD subunit (C‐I30 or NDUFS3) and altering its interaction with other proteins in the soluble matrix arm of C‐I involved in electron transfer. CPT was obtained from Cerepeut Inc. under a Materials Transfer Agreement between Cerepeut Inc. and Stanford University. The compound was synthesized for Cerepeut Inc. by the Chemistry Branch of Medicilon.

Osteoarthritis (OA) is the most common chronic joint disease that affects the knee or hip with symptoms including joint pain and dysfunction. OA treatment is a highly unmet medical need. Development of a disease-modifying OA drug (DMOAD) is challenging with no approved drugs on the market. Inhibition of ADATMS-4/5 is a promising OA therapeutics to target cartilage degradation and potentially can reduce joint pain and restore its normal function. Herein, researchers report the discovery and optimization of hydantoin-type ADAMTS-4/5 inhibitors featured by a novel isoindoline amide scaffold for the treatment of osteoarthritis. The most promising compound 18 showed high in vitro potency as an ADAMTS-4/5 inhibitor, good druglike properties, and oral bioavailability. Molecule 18 exhibited clear dose-dependent efficacy in two independent in vivo efficacy studies. Part of the compound synthesis was performed at Medicilon.

Acute respiratory distress syndrome (ARDS) is a critical respiratory illness associated with infection, autoimmunity, and injuries. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). Researchers applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling. BAY-1834845 and PF-06650833 are synthesize by Medicilon.

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. The in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer. Pharmacokinetics, toxicokinetics and anti-drug antibodies of YYB-101 in cynomolgus monkeys were conducted by the Test and Control Article Department of Medicilon Preclinical Research, LLC, in accordance with regulations outlined in the USDA Animal Welfare act and conditions specified in The Guide for the Care and Use of Laboratory Animals.

The N-methyl-D-aspartate receptor coagonist D-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). Phenylglycine (PG) analogs that are inhibitors of ASCT1 and ASCT2. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7–1.4; however, values for L-4OHPG and L-4ClPG were lower. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS. Pharmacokinetic studies in rats and mice indicated high bioavailability by intraperitoneal or subcutaneous routes, with t1/2 values that allowed the evaluation of compound effects by a single acute administration in the animal models. Surprisingly, L-4FPG showed good blood-brain barrier penetration, with brain-to-plasma ratios ranging from 0.7 to 1.4 in the rat and from 0.7 to 0.9 in the mouse. L-4OHPG and L-4ClPG had lower values. Pharmacokinetic studies in mice for L-4FPG, L-4OHPG, and L-4ClPG were performed by Medicilon.

Induced myeloid leukemia cell differentiation protein (MCL1) is a crucial member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. PRT1419 is a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To validate the therapeutic feasibility of MCL1 inhibition in clear cell Renal Cell Carcinoma (ccRCC), researchers sought to investigate PRT1419 in a cell-line derived xenograft (CDX) model of PBRM1-mutant ccRCC. OS-RC-2 harbors a missense mutation in the PBRM1 bromodomain as a potential system to model PBRM1 loss in vivo. Importantly, OS-RC-2 lacks PBRM1 protein expression and can be transplanted into nude mice, generating tumors with histopathological features which closely resemble clinical ccRCC. For the OS-RC-2 model, 1 x 106 OS-RC-2 cells were injected into the right flank of 6–9-week-old female BALB/c nude mice. When the tumors were ~200 mm3, mice were randomized into two groups. Animals were either treated with vehicle or 20 mg/kg of PRT1419 administered intravenously, once weekly for three weeks. Researchers observed 42% Tumor Growth Inhibition (TGI) in response to PRT1419 treatment. PRT1419 dosing was well tolerated with no notable body weight loss or behavioral changes. Altogether these findings suggest PBRM1 loss in ccRCC is associated with MCL1 dependency and sensitivity to MCL1 inhibition. CDX studies were performed at Medicilon (OS-RC-2). All studies were performed in accordance with animal research guidelines from Medicilon.