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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.

Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. SP-1-303 acts as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating estrogen receptor (ER) expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.

Vertical transmission accounts for most human immunodeficiency virus (HIV) infection in children, and treatments for newborns are needed to abrogate infection or limit disease progression. A hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the early establishment of a persistent viral reservoir1. Daily antiretroviral therapy (ART), the current standard of care, can reduce plasma viral load (PVL) to undetectable levels, but treatment interruption results in viral rebound. Being small molecules, ART drugs rapidly diffuse to distal sites; for instance, DTG was detectable at therapeutically relevant concentrations in colorectal tissue within 1 h of a single oral dose in a Phase I trial.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of kidney cancer and is believed to mainly originate from proximal tubular epithelial cells of the nephron. MTUS1 was significantly downregulated in ccRCC tissues, especially in metastatic tissues. Knockdown of MTUS1 decreased microtubule stability, whereas increased microtubule dynamics by promoting the ratio of unphosphorylated KIF2CS192 adapting to high motility of metastatic cancer cells. MTUS1 is a potent microtubule-stabilizing protein19, so we assessed the impact of MTUS1 knockdown on microtubule dynamics. MTUS1 regulates microtubule dynamics via promoting KIF2CS192 phosphorylation by Aurora B. Western blot and immunohistochemistry further confirmed significantly lower expression of SORBS2 protein in metastatic tissues than that in primary tissues and normal tissues.

Droxytryptamine (5-HT; serotonin) 5-HT3 receptor is an excitatory ligandgated ion channel expressed in for example the brain and the gastrointestinal tract. CSTI-300 as a selective, high affinity 5-HT3 receptor partial agonist. CSTI-300 was examined alongside the selective 5-HT3 receptor antagonist alosetron (which is also currently marketed as a therapeutic for IBS-d). Sub-cutaneous application of 5-hydroxytryptophan (5-HTP; 10 mg/kg) markedly increased the rat’s sensitivity to abdominal contractions. CSTI-300 and Alosetron displayed similar efficacy in a rodent in vivo model of IBS-d, measured by a reduction in colonic sensitivity. The experiments (Rat colon distension model of IBS-d) were carried out by Medicilon. The protocol complied with and was approved by the Institutional Animal Care and Use Committee and Medicilon is accredited by the NIH Office of laboratory Animal Welfare (OLAW) and AAALAC. Experiments (dog behavioural and emesis model) were performed by Medicilon. The protocol for the dog behavioural and emesis model complied with and was approved by the Institutional Animal Care and Use Committee.

Butenolide is a promising antifouling natural product. Rosin-based antifouling paint with the incorporation of butenolide, a promising antifoulant, possesses the potential to deter the settlement of marine organisms on submerged surfaces. Butenolide with a purity >99% was synthesized by Medicilon, Inc. (Shanghai, China).