Modulation of proteasome subunit selectivity of syringolins.

Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding ß5 and ß2 subunits.

Development of small molecule-drug conjugates based on derivatives of natural proteasome inhibitors that exhibit selectivity for PSMA-expressing cancer cells.

In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.

Frontline use of rituximab may prevent ADAMTS13 inhibitor boosting during caplacizumab treatment in patients with iTTP: post hoc analysis of a phase 2/3 study in Japan.

BACKGROUND: A recent Phase 2/3 study in Japanese patients showed that caplacizumab was effective in treating immune-mediated thrombotic thrombocytopenic purpura (iTTP), with a low rate of iTTP recurrence. ADAMTS13 activity is monitored weekly during caplacizumab treatment to guide discontinuation of caplacizumab and consequently avoid exacerbations or relapse. The aim of this study was to assess changes in ADAMTS13 activity/inhibitor levels during caplacizumab treatment in this patient population. METHODS: A post hoc analysis of the Phase 2/3 study in Japanese patients was conducted. Patients ≥ 18 years old with confirmed iTTP received 10 mg of caplacizumab daily in conjunction with therapeutic plasma exchange (TPE) and immunosuppression for 30 days post-TPE. Outcomes included time to recovery of ADAMTS13 activity, ADAMTS13 activity level at treatment end, incidence of ADAMTS13 inhibitor re-elevation (ie, inhibitor boosting) during treatment, time to platelet count recovery, number of days of TPE, and safety. Outcomes according to presence of inhibitor boosting were also assessed. RESULTS: Nineteen patients had confirmed iTTP and were included in this analysis. Median (95% confidence interval) time to recovery of ADAMTS13 activity to ≥ 10%, ≥ 20%, and ≥ 60% was 14.6 (5.9-24.8), 18.5 (5.9-31.8), and 47.5 (18.5-60.9) days, respectively. Median (range) ADAMTS13 activity level at caplacizumab treatment end was 62.0% (29.0-101.0). Nine patients had ADAMTS13 inhibitor boosting. Delayed response of ADAMTS13 activity was observed in patients with inhibitor boosting. The median time to platelet count response and median number of TPE days were shorter in patients with inhibitor boosting compared with patients without inhibitor boosting. Rituximab was administered to almost all patients with inhibitor boosting (88.9%), after completion of TPE. Patients without inhibitor boosting who were treated with rituximab received it prior to completion of TPE. Only one patient experienced a recurrence, which occurred shortly after caplacizumab discontinuation due to an adverse event. CONCLUSIONS: In patients with iTTP, caplacizumab with TPE and immunosuppression may reduce the risk of ADAMTS13 inhibitor boosting if rituximab is administered early in the iTTP treatment period. Early administration of rituximab in addition to caplacizumab may prevent iTTP recurrence with inhibitor boosting. TRIAL REGISTRATION: NCT04074187.

Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

[Multiple myeloma with IgH::MYC and multiple extramedullary lesions].

A 41-year-old woman with right shoulder pain was found to have multiple tumors with osteolysis and M-proteinemia. Abnormal plasma cells (CD38+, CD138+, Igλ≫κ) were detected in 1.4% of bone marrow nucleated cells, and G-banding analysis revealed a 46,XX,t (8;14), (q24;q32) karyotype in 4 of 20 cells analyzed. A biopsy specimen from an extramedullary lesion had a packed proliferation of aberrant plasmacytoid cells with positive IgH::MYC fusion signals on fluorescence in situ hybridization. The patient was diagnosed with symptomatic multiple myeloma and treated with the BLd regimen, which significantly reduced M protein levels. Extramedullary lesions were initially reduced, but increased again after four cycles. The lesions disappeared with subsequent EPOCH chemotherapy and radiation, and complete remission was confirmed. The patient was then treated with high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Complete remission was maintained for over one year with lenalidomide maintenance therapy. A solitary IgH::MYC chromosomal translocation is extremely rare in multiple myeloma and may be associated with high tumor proliferative capacity, multiple extramedullary lesions, and poor prognosis. Combined therapeutic modalities with novel and conventional chemotherapy and radiation might be a promising treatment strategy for patients with this type of multiple myeloma.

Sunlight-Driven Nitrate-to-Ammonia Reduction with Water by Iron Oxyhydroxide Photocatalysts.

The photocatalytic reduction of harmful nitrates (NO3-) in strongly acidic wastewater to ammonia (NH3) under sunlight is crucial for the recycling of limited nitrogen resources. This study reports that a naturally occurring Cl--containing iron oxyhydroxide (akaganeite) powder with surface oxygen vacancies (ß-FeOOH(Cl)-OVs) facilitates this transformation. Ultraviolet light irradiation of the catalyst suspended in a Cl--containing solution promoted quantitative NO3--to-NH3 reduction with water under ambient conditions. The photogenerated conduction band electrons promoted the reduction of NO3--to-NH3 over the OVs. The valence band holes promoted self-oxidation of Cl- as the direct electron donor and eliminated Cl- was compensated from the solution. Photodecomposition of the generated hypochlorous acid (HClO) produced O2, facilitating catalytic reduction of NO3--to-NH3 with water as the electron donor in the entire system. Simulated sunlight irradiation of the catalyst in a strongly acidic nitric acid (HNO3) solution (pH ∼ 1) containing Cl- stably generated NH3 with a solar-to-chemical conversion efficiency of ∼0.025%. This strategy paves the way for sustainable NH3 production from wastewater.

Heteroatom doping enables hydrogen spillover via H+/e- diffusion pathways on a non-reducible metal oxide.

Hydrogen spillover, the simultaneous diffusion of protons (H+) and electrons (e-) is considered to be applicable to ubiquitous technologies related to hydrogen but limited to over reducible metal oxides. The present work demonstrates that a non-reducible MgO with heteroatom Al dopants (Al-MgO) allows hydrogen spillover in the same way as reducible metal oxides. Furthermore, a H+ storage capacity of this material owing to hydrogen spillover is more than three times greater than those of various standard metal oxides based on H+ transport channels within its bulk region. Atomic hydrogen diffuses over the non-reducible Al-MgO produces active H+-e- pairs, as also occurs on reducible metal oxides, to enhance the catalytic performance of Ni during CO2 hydrogenation. The H+ and e- diffusion pathways generated by the heteroatom Al doping are disentangled based on systematic characterizations and calculations. This work provides a new strategy for designing functional materials intended to hydrogen spillover for diverse applications in a future hydrogen-based society.

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent.

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

Photoinduced dual bond rotation of a nitrogen-containing system realized by chalcogen substitution.

Photoinduced concerted multiple-bond rotation has been proposed in some biological systems. However, the observation of such phenomena in synthetic systems, in other words, the synthesis of molecules that undergo photoinduced multiple-bond rotation upon photoirradiation, has been a challenge in the photochemistry field. Here we describe a chalcogen-substituted benzamide system that exhibits photoinduced dual bond rotation in heteroatom-containing bonds. Introduction of the chalcogen substituent into a sterically hindered benzamide system provides sufficient kinetic stability and photosensitivity to enable the photoinduced concerted rotation. The presence of two different substituents on the phenyl ring in the thioamide derivative enables the generation of a pair of enantiomers and E/Z isomers. Using these four stereoisomers as indicators of which bonds are rotated, we monitor the photoinduced C-N/C-C concerted bond rotation in the thioamide derivative depending on external stimuli such as temperature and photoirradiation. Theoretical calculations provide insight on the mechanism of this selective photoinduced C-N/C-C concerted rotation.

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study.

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Alemtuzumab monotherapy for T-cell prolymphocytic leukemia: an observational study in Japan.

Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT or bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced Epstein‒Barr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.

Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

The MraY Inhibitor Muraymycin D2 and Its Derivatives Induce Enlarged Cells in Obligate Intracellular Chlamydia and Wolbachia and Break the Persistence Phenotype in Chlamydia.

Chlamydial infections and diseases caused by filarial nematodes are global health concerns. However, treatment presents challenges due to treatment failures potentially caused by persisting Chlamydia and long regimens against filarial infections accompanied by low compliance. A new treatment strategy could be the targeting of the reduced peptidoglycan structures involved in cell division in the obligate intracellular bacteria Chlamydia and Wolbachia, the latter being obligate endosymbionts supporting filarial development, growth, and survival. Here, cell culture experiments with C. trachomatis and Wolbachia showed that the nucleoside antibiotics muraymycin and carbacaprazamycin interfere with bacterial cell division and induce enlarged, aberrant cells resembling the penicillin-induced persistence phenotype in Chlamydia. Enzymatic inhibition experiments with purified C. pneumoniae MraY revealed that muraymycin derivatives abolish the synthesis of the peptidoglycan precursor lipid I. Comparative in silico analyses of chlamydial and wolbachial MraY with the corresponding well-characterized enzyme in Aquifex aeolicus revealed a high degree of conservation, providing evidence for a similar mode of inhibition. Muraymycin D2 treatment eradicated persisting non-dividing C. trachomatis cells from an established penicillin-induced persistent infection. This finding indicates that nucleoside antibiotics may have additional properties that can break bacterial persistence.

Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.