Scaffold hopping via ring opening enables identification of acyclic compounds as new complement Factor D inhibitors.

The three complement pathways comprising the early phase of the complement system (the classical, lectin, and alternative pathways) act together with the innate and adaptive immune systems to protect against foreign entities and maintain tissue homeostasis. While these systems are normally under tight regulatory control, several diseases have been reported to correlate with uncontrolled activation and amplification of the alternative pathway, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. Complement FactorD (CFD), a serine protease, is the rate-limiting enzyme for the activity of alternative pathway. CFD activates the alternative pathway by cleaving Complement Factor B complexed to C3b (C3bB) to generate alternative pathway C3 convertase (C3bBb). In our search for novel CFD inhibitors with therapeutic potential, we employed a hot-spot analysis of an ensemble of apo and holo CFD structures. This analysis identified potential pharmacophore features that aided in the design of a series of compounds based on an l-proline core. While these compounds inhibited CFD in an esterolytic assay (for example, a proline-based compound, IC50 = 161 nM), the pharmacokinetic (PK) properties were poor. A strategy of scaffold hopping via ring opening led to a novel series of acyclic compounds, with subsequent structure-based ligand design and lead optimization producing several novel CFD inhibitors. One of these inhibitors, 1-(2-((2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-5-(3-methyl-3-(1-methylpiperidin-4-yl)ureido)-1H-indazole-3-carboxamide, showed good potency with IC50s of 37 nM in the esterolytic assay and 30 nM in a hemolytic assay and PK assessments following oral administration to rats revealed a Cmax of 113 ng/mL and an AUC0-24h of 257 hr.ng/mL.

Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon.

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50,000 individuals worldwide. Berotralstat (BCX7353) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors. Lead compound was identified as a potent inhibitor following a detailed lead optimization process that balanced the lipophilic efficiency (LipE) and pharmacokinetic (PK) profile.

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma.

Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.

Isosteres of ester derived glucose uptake inhibitors.

Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.

[Clinical and genetic analysis of a patient with Krabbe disease presented as peripheral neuropathy].

OBJECTIVE: To explore the clinical, electrophysiological and imaging features of a patient with Krabbe disease caused by GALC mutation. METHODS: A comprehensive analysis including clinical investigation and genetic testing was carried out. RESULTS: The patient presented with peripheral neuropathy with electrophysiological anomaly suggestive of asymmetric demyelinating neuropathy. Brain imaging revealed leukoencephalopathy. Genetic analysis has identified compound heterozygous mutations in exons 5 and 11 of the GALC gene, namely c.461C>A and c.1244G>A. CONCLUSION: Krabbe disease is a group of disorders featuring substantial phenotypic heterogeneity. Genetic and enzyme testing has become indispensable for accurate diagnosis for this disease.

Dose effects of mycophenolate mofetil in Chinese patients with neuromyelitis optica spectrum disorders: a case series study.

BACKGROUND: Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a devastating autoimmune inflammatory disorder of the central nervous system, which can result in blindness or paralysis. Currently, there is a dire need for new treatment options in the clinic. Several case series have shown that mycophenolate mofetil (MMF) may be an effective treatment for NMOSD patients. The dosing of MMF in the treatment of NMOSD has been poorly studied. Therefore, we evaluated the efficacy, tolerability, influential factors and optimal dosage of MMF in Chinese patients with NMOSD. METHODS: A case series of 109 NMO or NMOSD (limited forms of NMO with seropositive AQP4-IgG) patients were retrospectively analyzed and followed up. Out of the 109 patients, 86 patients had received MMF for 6 months or longer and were included for efficacy assessment. RESULTS: When comparing the annualized relapse rate (ARR) of MMF treatment with that of pre-MMF treatment period, MMF was found to significantly reduce ARR in 75 (87%) patients (p < 0.0001). The median pre-treatment Expanded Disability Status Scale (EDSS) score in remission decreased from 3 (range, 0-8.5) to 2.5 (range, 0-8) at the last follow-up (p = 0.006), yet no significant difference was found in the visual score. The higher doses of MMF (1750 mg/d to 2000 mg/d) significantly lowered the relapse risks compared with lower doses (1000 mg/d or less, p < 0.0001) or moderate doses (1250 to 1500 mg/d, p = 0.031). Coexisting with systemic autoimmune diseases (HR, 2.418; p = 0.0345) and attack number before MMF initiation (HR, 1.117; p = 0.02) were important risk factors for relapses. MMF was generally well tolerated with adverse effects occurring in 21 patients (19%). While four patients decreased their daily doses because of the adverse effects, only one patient stopped MMF treatment. CONCLUSIONS: MMF is generally effective and well tolerated in Chinese NMOSD patients. High-dose MMF was more potent than the lower dose for NMOSD patients, with 1750 mg of daily MMF being the recommended dosage for Chinese patients with NMOSD. MMF treatment reduces the frequency of relapses and improves the quality of life for patients with this debilitating disease.

Recent Thymus Emigrant CD4+ T Cells Predict HIV Disease Progression in Patients With Perinatally Acquired HIV.

BACKGROUND: Robust immune restoration in human immunodeficiency virus (HIV)-positive patients is dependent on thymic function. However, few studies have investigated thymic function and its correlation with disease progression over time in HIV-positive patients. METHODS: In this longitudinal prospective study, we followed 69 HIV-positive patients who were perinatally infected. Peripheral blood mononuclear cells were stained with monoclonal anti-CD4 and anti-CD31 and recent thymic emigrants (CD4+recently emigrated from the thymus (RTE), CD4+CD31+) quantified by flow cytometry. Statistical analysis used Wilcoxon rank sum test, Kruskal-Wallis, Spearman correlation, and Kaplan-Meier estimates; Cox regression models were performed for the longitudinal analysis. RESULTS: Median age of HIV positive patients enrolled was 13 years (interquartile range [IQR], 8.6). CD4+RTE% decreased with age and was higher in females. Median CD4+RTE% was 53.5%, IQR, 22.9. CD4+RTE% was closely related to CD4+% and absolute counts but independent of viral load and CD8+CD38+%. Antiretroviral compliance as well as higher nadir CD4+% were associated with higher CD4+RTE%. Low CD4+RTE% predicted poor progression of VL and CD4+% over time. CONCLUSIONS: CD4+RTE% predicts disease progression and may reflect history of disease in HIV-positive patients and adolescents. They are easy to measure in the clinical setting and may be helpful markers in guiding treatment decisions.

[An analysis of clinical and imaging characteristics of atopic myelitis].

OBJECTIVE: To study the clinical and imaging characteristics of Chinese atopic myelitis (AM) patients. METHODS: Three diagnosed AM patients were retrospectively analyzed for the clinical data, serum IgE level, antigen specific IgE, cerebrospinal fluid, spinal MRI and therapeutic efficacy profiles. RESULTS: All the three patients were male and presented as subacute AM with the onset at 25, 47 and 49 years old respectively. Two patients were allergic to pollen and other drugs, while another patient suffered from allergic rhinitis. Elevated serum total IgE and mite antigen specific IgE were found in all cases. Paraesthesia in limb extremities and positive Lhermitte sign were the main clinical features, while no optic, motor, urinary and defecation disturbance were found. Oligoclonal banding of cerebrospinal fluid and serum aquaporin 4 (AQP4) antibody were both negative in all cases. Spinal MRI showed lesions were hypointense on T1 and hyperintense on T2 at the posterior column of T2-3 segment with abnormal enhancement in case 1, hypointense on T1 and hyperintense on T2 at C2/3 segment with mild swelling in case 2 and hypointense on T1 and hyperintense on T2 at C3-5 segments with swelling and abnormal enhancement in case 3. Vitamin B were used in one patient, while the other two patients improved after the treatment with high-dose corticosteroids. CONCLUSIONS: Subacute myelitis predominantly presents as paraesthesia in limb extremities with elevated serum total IgE and mite antigen specific IgE, while severe motor disorders are rare. Swelling and abnormal enhancement lesions at the posterior column of cervical cord are the common imaging features. Treatment with corticosteroids is recommended to be sustained for 3-6 months.

[Serum uric acid level and clinical relevance analysis in autoimmune myelopathy].

OBJECTIVE: To quantify serum uric acid (UA) levels in autoimmune myelopathy (AMs) patients and analyze the clinical relevance. METHODS: Blood samples from hospitalized patients with AMs (n = 69) in acute phase and other neurological disorders (n = 50) between September 2009 and December 2013 and healthy subjects (n = 50) were used to detect UA level by enzymatic calorimetric method.Expanded disability status scale (EDSS) and spinal MRI-T2 imaging were used for clinical and imaging severity evaluations.And serum AQP4 anitbody and other antibodies were tested. RESULTS: Serum UA level in AMs patients ((223 ± 76) µmol/L) was lower than in controls ((325 ± 53) µmol/L and (324 ± 48) µmol/L, P < 0.001); for clinical relevance analysis, serum UA levels in females ((208 ± 64) µmol/L), age ≥ 40 years ((185 ± 64) µmol/L), EDSS score ≥ 4.5 ((179 ± 59) µmol/L), transverse lesion ((179 ± 56) µmol/L) and neuromyelitis optica/spectrum disorders ((199 ± 70) µmol/L) were lower than in males ((252 ± 88) µmol/L, P < 0.05), age < 40 years ((266 ± 66) µmol/L, P < 0.001), EDSS score < 4.5 ((257 ± 70) µmol/L, P < 0.001), non-transverse lesion ((274 ± 64) µmol/L, P < 0.001) and multiple sclerosis ((261 ± 69) µmol/L, P < 0.05). An inverse correlation existed between UA level and involved spinal segments (r = -0.665, P < 0.001); status of serum antibodies and associated diseases showed no significant differences. CONCLUSION: Serum UA level is low and shows strong relevance with clinical and imaging severity in AMs patients. And UA is recommended as a biomarker of AMs.

[Analysis of clinical features for 8 patients with autoimmune dementia].

OBJECTIVE: To explore the clinical features and therapeutic profiles of autoimmune dementia. METHODS: Eight hospitalized patients with autoimmune dementia during March 2011 and May 2013 were recruited and retrospectively analyzed for clinical features, as well as therapeutic and prognosis profiles. RESULTS: There were 3 males and 5 females with a onset age range of 45-72 years. Their onsets varied from acute (n = 3), subacute (n = 1) to chronic (n = 4).Six of them had a fluctuating course. The diagnoses were multiple sclerosis (n = 3), paraneoplastic limbic encephalitis (n = 2) and Hashimoto's encephalopathy (n = 1), microscopic polyangiitis (n = 1) and unclassified autoimmune encephalopathy (n = 1). Progressive memory loss without delirium was the main symptom.In addition, 3 patients suffered epilepsy, 2 with intractable hyponatremia, 4 with positive serum autoimmune or paraneoplastic antibodies, 7 with inflammatory cerebrospinal fluid, 4 with abnormal electroencephalography (EEG) and 8 with various changes on brain magnetic resonance imaging (MRI). Two patients had concurrent Hashimoto's thyroiditis and another with small cell lung cancer. All patients improved after treatment with immunological and antineoplastic therapies. CONCLUSION: Autoimmune dementia has complex causes with a rapidly progressive and fluctuating course. The coexisting conditions include epilepsy, hyponatremia, organ-specific autoimmunity, inflammatory spinal fluid with abnormal EEG and brain MRI findings.Immunotherapy is recommended.

[Longitudinally extensive spinal cord lesion: etiology and imaging features].

OBJECTIVE: To explore the etiologies and imaging features of longitudinally extensive spinal cord lesion (LESCL). METHODS: The etiologies and magnetic resonance (MR) imaging features of 51 hospitalized LESCL patients from January 2011 to August 2013 were reviewed and retrospectively analyzed. RESULTS: Among them, the causes were neuromyelitis optica spectrum disorder (NMOSD, n = 25), isolated longitudinally extensive transverse myelitis (n = 6), subacute combined degeneration (n = 4), multiple sclerosis (MS, n = 3), paraneoplastic myelopathy (n = 3), anterior spinal artery syndrome (n = 3), acute disseminated encephalomyelitis (n = 2), spinal dural arteriovenous fistula (n = 2), intramedullary spinal cord metastasis (n = 1), myelopathic leukemia (n = 1) and syringomyelus (n = 1). For MR imaging, at least one lesion of each patient presented continuously longitudinal profile and whole-length spinal cord was involved in 11 patients. CONCLUSION: LESCL may be caused by various diseases. And the imaging features may aid its diagnosis despite a lack of specificity.

FCGR3A-V158F gene polymorphism: A potential predictor for rituximab dosing optimization in Chinese patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown promise in managing neuromyelitis optica spectrum disorders (NMOSD) by depleting B cells and reducing relapses. However, there is no consensus on the optimal RTX dosing regimen, and genetic factors, such as FCGR3A-V158F polymorphism, may influence treatment outcomes. This study investigates how FCGR3A-V158F genotypes influence RTX efficacy in Chinese NMOSD patients under varying dosing regimens and aims to optimize treatment protocols. METHODS: We conducted a retrospective analysis of 25 Chinese NMOSD patients treated with RTX, grouped into standardized and low-dosage regimens. FCGR3A-V158F genotypes were determined, and treatment responses were evaluated, including relapse rates, time to first relapse (TFR), B-cell depletion, dose adjustments, and treatment retention. RESULTS: Among all patients, 15 received standardized dosages, while 10 received varied induction doses (500 mg to 1200 mg) in low-dose regimens. For FCGR3A-V158F genotypes, 15 had the FF genotype, and 10 were V carriers (3 VV genotype, 7 VF genotype). Regardless of dosing, FF genotype patients had a higher relapse rate post-RTX treatment compared to V carriers (P < 0.05). None of the 3 VV genotype patients in either dose group experienced relapses post-RTX. In both dose groups, FF genotype patients had significantly shorter TFR and required more RTX dose adjustments post-RTX treatment compared to V carriers in the standardized dosage group (P < 0.05). FF genotype patients in the low dosage group were more likely to experience insufficient B-cell depletion, had lower treatment retention rates, and more discontinuations than V carriers in the standardized dosage group (P < 0.05). Insufficient B-cell depletion significantly predicted clinical relapses after RTX treatment (P < 0.05). In survival analysis, FF genotype patients, regardless of dosing, experienced earlier relapses post-RTX treatment (P < 0.05). CONCLUSIONS: This study highlights the importance of RTX dosage selection in NMOSD treatment, particularly for FCGR3A-FF genotype patients. Standard-dose RTX therapy with vigilant monitoring of peripheral blood B-cell levels is recommended for these individuals to optimize treatment efficacy.

Bedaquiline susceptibility testing of Mycobacterium abscessus complex and Mycobacterium avium complex: A meta-analysis study.

OBJECTIVE: This study aims to estimate the overall in vitro activity of bedaquiline (BDQ) against clinical isolates of Mycobacterium abscessus complex (MABS) and M. avium complex (MAC), considering BDQ as a repurposed drug for non-tuberculous mycobacteria (NTM) infections. METHODS: We conducted a systematic review of publications in PubMed/ MEDLINE, Web of Science, and Embase up to 15 April 2023. Studies were included if they followed the Clinical and Laboratory Standards Institute (CLSI) criteria for drug susceptibility testing (DST). Using a random effects model, we assessed the overall in vitro BDQ resistance rate in clinical isolates of MABS and MAC. Sources of heterogeneity were analysed using Cochran's Q and the I2 statistic. All analyses were performed using CMA V3.0. RESULTS: A total of 24 publications (19 reports for MABS and 11 for MAC) were included. Using 1 µg/mL and 2 µg/mL as the breakpoint for BDQ resistance, the pooled rates of in vitro BDQ resistance in clinical isolates of MABS were found to be 1.8% (95% confidence interval [CI], 0.7-4.6%) and 1.7% (95% CI, 0.6-4.4%), respectively. In the case of MAC, the pooled rates were 1.7% (95% CI, 0.4-6.9%) and 1.6% (95% CI, 0.4-6.8%) for 1 µg/mL and 2 µg/mL, respectively. CONCLUSION: This study reports the prevalence of BDQ resistance in clinical isolates of MABS and MAC. The findings suggest that BDQ holds potential as a repurposed drug for treating MABS and MAC infections.

Therapeutic efficacy and safety of plasmapheresis in elderly patients with neuromyelitis optica spectrum disorder: a single-center observational study.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disorder with cycles of escalating relapse. Rates of diagnosis in the elderly are increasing. Therapeutic decision-making is more challenging in elderly patients due to multiple comorbidities and high risk of drug-induced side effects. Objective: This retrospective study assessed the efficacy and safety of standard plasma exchange (PLEX) treatment in an elderly population with NMOSD. Design: Seventy-six patients with NMOSD who received PLEX were apportioned to two groups as either elderly (⩾60 years, n = 26) or young (<60 years) at the time of the first procedure. Methods: Therapeutic response was judged according to functional recovery at 6 months, as reflected by Expanded Disability Status Scale (EDSS) and visual outcome scale (VOS) scores. Results: The mean age of the 26 elderly patients was 67.7 ± 7.9 years (range 60-87 years); the population was predominantly female (88.5%). PLEX sessions were generally well tolerated among the elderly. Compared with the young patients, the elderly had significantly more comorbidities and concomitant medications. Twenty-four (96.0%) elderly patients showed functional improvement at 6 months after PLEX, of which 15 (60.0%) experienced moderate-to-marked improvement. Six months after the initial PLEX treatment, the patients overall experienced a significant improvement in EDSS and VOS scores. Logistic regression showed that severe optic neuritis attack was a significant independent prognostic factor associated with poor PLEX response. The groups were comparable regarding overall or serious adverse events. The rate of transient hypotension was significantly higher in the elderly compared with the young. Conclusion: PLEX is an effective and safe therapy for elderly patients with NMOSD and should be considered a treatment option during NMOSD attacks. In the elderly, preventive measures against hypotension are recommended before PLEX.

Successful treatment of rituximab-unresponsive elderly-onset neuromyelitis optica spectrum disorder and hypogammaglobulinemia with ofatumumab plus intravenous immunoglobulin therapy in a patient with mutant FCGR3A genotype: A case report.

Background: Elderly-onset neuromyelitis optica spectrum disorder (NMOSD) is a rare entity that poses a therapeutic challenge. We report a case of elderly-onset NMOSD with mutant FCGR3A genotype who was successfully treated with ofatumumab after multiple episodes of relapse. Case Report: The patient was a 67-year-old woman who was diagnosed with NMOSD with high disease activity. She experienced six episodes of relapse over a period of 2 years despite immunosuppressant therapy with intravenous rituximab (RTX), oral steroids, mycophenolate mofetil, and tacrolimus. At the last relapse, she was unable to walk and developed immunosuppressant-induced hypogammaglobulinemia. Based on the insufficient B cell depletion and FCGR3A-FF genotype carrier, the patient was diagnosed as RTX non-responder. After subcutaneous ofatumumab plus intravenous immunoglobulin replacement therapy, she was able to walk independently, and experienced no further relapse. Ofatumumab was well-tolerated, and sufficiently depleted the circulating B cells. Conclusion: Ofatumumab might be an effective alternative in RTX-unresponsive NMOSD, and seems to be safe in elderly patients.

[Clinical features of ultra longitudinally extensive transverse myelitis].

OBJECTIVE: To analyze the clinical features of ultra longitudinally extensive transverse myelitis (uLETM). METHODS: Four first-onset uLETM patients hospitalized during September 2009 and March 2011 were recruited and retrospectively analyzed for clinical and MRI (magnetic resonance imaging) features, as well as therapeutic profiles and prognoses. RESULTS: The male-to-female ratio was 1:3 and the age-of-onset 29 - 33 years old. Extremity paralysis and intrinsic sphincter disorders were initially observed. The clinical manifestations include visual, motor, sense and intrinsic sphincter disorders caused by optic nerve and spinal cord lesions. Uric acid decreased in 3 cases. Seropositivity for autoimmune antibody spectrum and NMO-IgG (neuromyelitis optica-immunoglobulin G) was found in some patients. Spinal MRI showed overall hypointense T1 and hyperintense T2 lesions in spinal cord with partial swelling and negative in brain MRI. Sjogren's syndrome associated with uLETM was diagnosed in 2 patients. Three cases improved after treatment with high-dose corticosteroids, intravenous immunoglobulin and other immunosuppressive agents. One patient died. CONCLUSION: uLETM is commonly found in young women. Spinal cord is frequently affected. And it may occur concurrently with optical abnormalities and other autoimmune diseases. Intracranial parenchyma is rarely affected. The therapy of corticosteroids is recommended.

Neurological Autoimmunity Associated With Homer-3 Antibody: A Case Series From China.

BACKGROUND AND OBJECTIVE: To present 6 new cases with Homer-3 antibodies that expand their clinical spectra and to evaluate the effect of immunotherapy. METHODS: Patients with suspected autoimmune cerebellar disorder were tested for rare autoimmune cerebellar ataxia (ACA) antibodies (anti-Tr(DNER)/Zic4/ITPR1/Homer-3/NCDN/PKCγ/PCA-2/AP3B2/mGluR1/ATP1A3 antibodies) using both cell-based and tissue-based assays. Patients with positive serum or CSF results who were diagnosed with ACA were registered and followed up. This study reports and analyzes cases with Homer-3 antibodies. RESULTS: Of the serum and CSF samples of 750 patients tested, 6 were positive for Homer-3 antibodies. All manifested subacute or insidious-onset cerebellar ataxia. Furthermore, 2 patients each exhibited encephalopathy, myeloradiculopathy, REM sleep behavior disorder, and autonomic dysfunction. Brain magnetic resonance images were normal (n = 1) or revealed cerebellar atrophy (n = 1), cerebellum and pons atrophy with the hot cross bun sign (n = 2), and bilateral cerebral abnormalities (n = 2). Definite leukocytosis was identified in the CSF of 2 patients, protein concentration elevation was observed in the CSF of 1 patient, and oligoclonal bands were present in 2 patients. All patients received immunotherapy, including corticosteroid, IV immunoglobulin, plasma exchange, and mycophenolate mofetil, after which the residual disability was still severe (modified Rankin Scale score ≥3 at the last follow-up in 4 patients and final Scale for the Assessment and Rating of Ataxia scores of 12-29), although 4 patients partially improved and 1 patient stabilized. The remaining 1 patient continued to deteriorate after repeated immunotherapy. Two patients relapsed. DISCUSSION: Disorders associated with Homer-3 antibody can mimic multiple system atrophy with cerebellar features in both clinical and radiologic aspects. Accurate identification of autoimmune-mediated cases is critical. Timely, comprehensive immunotherapy is warranted, given the possibility of long-term clinical benefit.

UNC5293, a potent, orally available and highly MERTK-selective inhibitor.

Inhibition of MER receptor tyrosine kinase (MERTK) causes direct tumor cell killing and stimulation of the innate immune response. Therefore, MERTK has been identified as a therapeutic target in a wide variety of human tumors. Clinical trials targeting MERTK have recently been initiated, however, none of these drugs are MERTK-specific. Herein, we present the discovery of a highly MERTK-selective inhibitor UNC5293 (24). UNC5293 has subnanomolar activity against MERTK with an excellent Ambit selectivity score (S50 (100 nM) = 0.041). It mediated potent and selective inhibition of MERTK in cell-based assays. Furthermore, it has excellent mouse PK properties (7.8 h half-life and 58% oral bioavailability) and was active in bone marrow leukemia cells in a murine model.

Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

Discovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).