Machine Learning ADME Models in Practice: Four Guidelines from a Successful Lead Optimization Case Study.

Optimization of the ADME properties and pharmacokinetic (PK) profile of compounds is one of the critical activities in any medicinal chemistry campaign to discover a future clinical candidate. Finding ways to expedite the process to address ADME/PK shortcomings and reduce the number of compounds to synthesize is highly valuable. This article provides practical guidelines and a case study on the use of ML ADME models to guide compound design in small molecule lead optimization.

Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS Inhibitor.

Oncogenic mutations in the gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS covalent inhibitor currently in phase I clinical trials (NCT05067283).

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors.

Hyperlactatemia in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest: Risk factors and its effects on the outcome.

Introduction: To determine the risk factors of hyperlactatemia in pulmonary endarterectomy (PEA) surgery and assess whether elevated blood lactate levels are associated with adverse outcomes.

Methods: In this retrospective observational study, a total of 111 consecutive patients who underwent PEA for chronic thromboembolic pulmonary hypertension at the XXX Hospital between December 2016 and January 2022 were included. We retrospectively evaluated arterial blood samples analyzed intraoperatively.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs).

[Risk factors of hyperlactatemia during pulmonary endarterectomy under deep hypothermic circulatory arrest and its influence on prognosis].

To investigate the incidence, risk factors, and outcomes of hyperlactatemia after pulmonary endarterectomy (PEA) under deep hypothermic circulatory arrest (DHCA). From December 2016 to January 2022, patients receiving PEA in China-Japan Friendship Hospital were enrolled in the study. Arterial blood samples were analyzed intraoperatively.

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS).

Utilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors.

Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).

Discovery of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold.

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined.

WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored.

Combination of EP antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells.

Prostaglandin E (PGE), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP receptor.

Role of pyroptosis in atherosclerosis and its therapeutic implications.

Atherosclerosis is a significant cardiovascular burden and a leading cause of death worldwide, recognized as a chronic sterile inflammatory disease. Pyroptosis is a novel proinflammatory regulated cell death, characterized by cell swelling, plasma membrane bubbling, and robust release of proinflammatory cytokines (such as interleukin IL-1β and IL-18). Mounting studies have addressed the crucial contribution of pyroptosis to atherosclerosis and clarified the candidate therapeutic agents targeting pyroptosis for atherosclerosis.

Carbamate and -Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds.

Selective Synthesis of 1-Dialkylamino-2-alkylbicyclo-[1.1.1]pentanes.

Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), the synthetic accessibility of BCPs with substitutions at the methylene position has been limited.

Surgical treatment of primary pulmonary artery sarcoma.

Objective: Primary pulmonary artery sarcoma (PAS) is a rare tumor that originates from the intimal layer of the pulmonary artery or pulmonary valve and has a poor prognosis. The standard treatment for this devastating disease remains unclear. This study aimed to summarize the current standard treatments for PAS.

Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1.

Impact of pulmonary thromboendarterectomy on tricuspid regurgitation in patients with chronic thromboembolic pulmonary hypertension: a single-center prospective cohort experience.

Background: For patients with chronic thromboembolic pulmonary hypertension (CTEPH) and tricuspid regurgitation (TR) undergoing pulmonary thromboendarterectomy (PTE), whether concomitant tricuspid annuloplasty should be carried out is still controversial.

Methods: The study population consisted of 45 consecutive patients with CTEPH who were scheduled to undergo PTE. All PTE surgeries were conducted with a median sternotomy and deep hypothermia circulatory arrest (DHCA).

Small Molecular Immune Modulators as Anticancer Agents.

After decades of intense effort, immune checkpoint inhibitors have been conclusively demonstrated to be effective in cancer treatments and thus are revolutionizing the concepts in the treatment of cancers. Immuno-oncology has arrived and will play a key role in cancer treatment in the foreseeable future. However, efforts to find novel methods to improve the immune response to cancer have not ceased.

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors.

A Selective Synthesis of 2,2-Difluorobicyclo[1.1.1]pentane Analogues: "BCP-F".

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, -butyl, and alkynyl fragments in order to improve physicochemical properties.

An osteoclast-like giant cell tumor embedded in the mural nodule of a pancreatic mucinous cystic neoplasm: A case report and literature review.

Rationale: Mucinous cystic neoplasms (MCNs) are relatively rare lesions, accounting for 2%-5% of all exocrine pancreatic neoplasms. MCNs mainly occur in women (female:male ratio = 20:1), with a peak incidence in the 5th decade of life. Osteoclast-like giant cell tumors (OGCTs) are rare and relatively aggressive neoplasms, comprising <1% of all pancreatic carcinomas.

Repurposing a Histamine Detection Platform for High-Throughput Screening of Histidine Decarboxylase.

Histidine decarboxylase (HDC) is the primary enzyme that catalyzes the conversion of histidine to histamine. HDC contributes to many physiological responses as histamine plays important roles in allergic reaction, neurological response, gastric acid secretion, and cell proliferation and differentiation. Small-molecule modulation of HDC represents a potential therapeutic strategy for a range of histamine-associated diseases, including inflammatory disease, neurological disorders, gastric ulcers, and select cancers.

CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent and Efficacy in the Treatment of Chronic Myeloid Leukemia.

Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors.