Aim:The purpose of the current study was to explore the virtual library for the screening against Monoamine oxidase (MAO) isoforms. An in-house library of natural based ligands was docked within the active sites of MAO isoforms and their in vitro study was also conducted.Objective:The prime objective of the current study was to screen and validate the natural-based derivatives for MAO inhibitory action with the least adverse effects and get molecular aspects about further structural modifications on the most active leads.Background:The importance of MAOs in controlling the activity of the central nervous system has been extensively studied. Our goal in this work is to identify a prospective natural lead molecule that has a stronger affinity for the MAO enzyme in order to produce a more effective natural candidate for a neurological agent.Methods and Results:In order to get insight into how different categories of natural compounds interact with the targeted protein, we virtually screened the numerous natural compound categories in the current study. Rhamnetin, quercetin, piperine, eugenol, and umbelliferone showed the highest dock scores in the case of MAO-B, with scores of -10.57, -9.938, -9.445, and 7.821, respectively. For MAO-A, umbelliferone, curcumin, caffeic acid, and quercetin, the corresponding dock scores were -8.001, -7.941, -7.357, and -6.658. Additionally, an in vitro MAO inhibitory experiment was utilized to assess the top-ranked compounds with the best docking scores. The most potent Human Monoamine oxidase (hMAO-A) inhibitor, with an IC50 of 10.98±0.006 M and a selectivity index (SI) of 0.607, was discovered to be the compound umbelliferone. Rhamnetin, the lead chemical, has demonstrated hMAO-B activity with a value of 10.32±0.044 M (SI value of 3.096).Conclusion:These natural potential ligands have been found remarkable to the standard compounds against MAO-A and MAO-B, and they could be used as a lead chemical in the development of novel therapeutic candidates. The in silico screening results and in vitro hMAO inhibitory efficacy exhibited strong correlations.

01 Nov 2024·Journal of Biomolecular Structure and Dynamics

Phytochemicals-based β-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer’s disease: molecular simulations-based predictions

Article

Author: Khan, Haider Ali ; Alyami, Bandar A. ; Alqahtani, Omaish ; Mahnashi, Mater H. ; Ghufran, Mehreen ; Almazni, Ibrahim Abdullah ; Alqahtani, Yahya S. ; Waqas, Muhammad ; Sadiq, Abdul ; Ayaz, Muhammad

Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features.Communicated by Ramaswamy H. Sarma.

01 Nov 2024·International Journal of Biological Macromolecules

Development of potential cathepsin B inhibitors: Synthesis of new bithiazole derivatives, in vitro studies supported with theoretical docking studies

Article

Author: Pundeer, Rashmi ; Raghav, Neera ; Vashisth, Chanchal ; Yadav, Sidhant ; Singh, Karan ; Chaudhri, Vishwas

Cysteine cathepsins play a crucial role in cancer, inflammation, and the regulation of degenerative processes such as apoptosis, making them significant targets in drug development. In this study, we designed, synthesized, and characterized sixteen novel bi-thiazole derivatives, confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray analysis, which demonstrated significant therapeutic potential as inhibitors of cathepsin B. The synthesized thiazoles showed % inhibition in the range of 59.11-77.32, out of which bis-methoxyphenyl derivative 8k showed the highest inhibition of 77.32 % with IC₅₀ and k_i values of 1.04 nM and 0.52 nM, respectively. Methoxy-containing derivatives 8c, 8g, 8i, 8j, 8l, and 8o showed improved inhibition over methyl and chloro. In silico studies of the new bis-thiazole compounds at cathepsin B active sites supported the in vitro findings, indicating that the synthesized bis-thiazole esters are promising therapeutic candidates for conditions involving elevated cathepsin B levels.

News (Medical) associated with PF-9601N

06 Dec 2023

·www.pmlive.com

Novartis’ Fabhalta approved by FDA as first oral monotherapy for rare blood disease PNH

Novartis’ Fabhalta (iptacopan) has been approved by the US Food and Drug Administration (FDA) as the first oral monotherapy for adults with paroxysmal nocturnal haemoglobinuria (PNH), a rare blood disease affecting approximately ten to 20 people per million worldwide. PNH patients have an acquired mutation that causes them to produce red blood cells susceptible to premature destruction by the complement system, which can cause anaemia, thrombosis, fatigue and other symptoms that can impact quality of life. The disease has a significant unmet need, Novartis reports, with a large proportion of patients on anti-C5 treatment remaining anaemic and dependent on blood transfusions. Fabhalta is a factor B inhibitor of the immune system’s complement pathway and offers an alternative to therapies that need to be delivered by infusion or injection. Victor Bultó, president US, Novartis, described the approval as an "extraordinary moment” for the PNH community. "This new, effective oral medicine may mean that patients can reset their expectations of living with PNH,” he said. The FDA’s decision on the drug, which applies to both previously treated and treatment-naïve patients, was based on the late-stage APPLY-PNH trial in adults with PNH and residual anaemia despite prior anti-C5 treatment. Results showed that patients who switched to Fabhalta experienced superior increases of haemoglobin levels over those who continued on anti-C5 treatment. The approval was also supported by positive results from the phase 3 APPOINT-PNH study in complement inhibitor-naïve patients, Novartis said. “In clinical studies, [Fabhalta] was superior to anti-C5s in haemoglobin improvement in the absence of red blood cell transfusion and transfusion avoidance rate, and also effective in complement inhibitor-naïve individuals, by providing clinically meaningful haemoglobin-level increases without the need for blood transfusions,” said Vinod Pullarkat, clinical professor in the department of haematology and haematopoietic cell transplantation at City of Hope, US. Bultó outlined that the company is exploring the potential of Fabhalta in other complement-mediated diseases “with an ultimate goal to drive meaningful change for patients”. The approval comes just over a month after Novartis’ Cosentyx (secukinumab) was approved by the FDA to treat adults with moderate-to-severe hidradenitis suppurativa (HS). The decision makes the IL-17A inhibitor, which is currently approved to treat a range of inflammatory conditions, the first biologic treatment approved for HS in nearly a decade.

Drug ApprovalClinical ResultPhase 3

20 Nov 2023

·www.biospace.com

Novartis showcases significant data updates from Kisqali®, iptacopan and Scemblix® at SABCS and ASH

Late-breaking final iDFS analysis from NATALEE investigating Kisqali® (ribociclib) in broad population of patients with stage II and III HR+/HER2- early breast cancer, including those with node-negative disease New 48-week efficacy and safety data from the Phase III APPLY-PNH trial of investigational oral monotherapy iptacopan in anti-C5-treated adult patients with paroxysmal nocturnal hemoglobinuria (PNH) and persistent anemia Nearly 4 year follow-up efficacy and safety results from end of study treatment update ofASCEMBL with Scemblix® (asciminib) in patients with Ph+ chronic phase-chronic myeloid leukemia (CP-CML) after ≥2 Prior Tyrosine Kinase Inhibitors Basel, November 20, 2023 — Novartis will present data from over 100 trials across its breast cancer and hematology portfolios at the 2023 San Antonio Breast Cancer Symposium (SABCS) and the American Society of Hematology (ASH) Annual Meeting & Exposition. The new data will highlight the latest advances across our breast cancer and hematology portfolios and pipeline, such as the Phase III NATALEE trial and Phase III APPLY-PNH trial. “We’re developing new therapies across a range of cancers and blood disorders as well as evaluating the potential of our priority medicines in earlier stages of disease,” said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis. “Among the new findings we will present at SABCS and ASH this year are additional follow-up Kisqali data from NATALEE, adding to the body of evidence of ribociclib in early breast cancer, as well as new 48-week data from the Phase III APPLY-PNH trial for iptacopan.” Key highlights of data accepted by SABCS include: Medicine Abstract Title Abstract Number/ Presentation Details Kisqali® (ribociclib)* Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial Abstract #GS03-03 Oral Presentation Friday, December 8 8:15 – 11:15 AM CT Kisqali® (ribociclib)* Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis Abstract #PO1-17-07 Poster Session Wednesday, December 6 12:00 – 2:00 PM CT Kisqali® (ribociclib)* Patient preferences for CDK4/6 inhibitor treatments in HR+/HER2− early breast cancer: a discrete choice survey study Abstract #PO2-01-09 Poster Session Wednesday, December 6 5:00 – 7:00 PM CT Key highlights of data accepted by ASH include: Medicine or Disease State Abstract Title Abstract Number/ Presentation Details Iptacopan (LNP023) Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial Abstract #571 Oral Presentation Sunday, December 10 4:30 PM PT Iptacopan (LNP023) Patient-Reported Improvements in Fatigue and Health-Related Quality of Life in the Phase 3 Studies APPLY-PNH and APPOINT-PNH Evaluating the Use of Iptacopan in C5 Inhibitor-Treated and Treatment-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria Abstract #487 Oral Presentation Sunday, December 10 9:30 AM PT Iptacopan (LNP023) Categorization of Hematological Responses to Oral Iptacopan Monotherapy in Anti-C5-Treated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia in the Phase III APPLY-PNH Trial and Complement Inhibitor-Naïve Patients in the Phase III APPOINT-PNH Trial Abstract #4084 Poster Presentation Monday, December 11 6:00 – 8:00 PM PT Iptacopan (LNP023) Clinical Breakthrough Hemolysis (BTH) during Monotherapy with the Oral Factor B Inhibitor Iptacopan Is Generally Not Severe and Managed without Treatment Discontinuation: 48-Week Data from the Phase III APPLY-PNH and APPOINT-PNH Trials in Paroxysmal Nocturnal Hemoglobinuria (PNH) Abstract #1338 Poster Presentation Saturday, December 9 5:30 – 7:30 PM PT Scemblix® (asciminib) Sustained Efficacy and Safety with Asciminib (ASC) after Almost 4 Years of Median Follow-up from ASCEMBL, a Phase 3 Study of ASC vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): An End of Study Treatment (EOS Tx) Update, Including Results from Switch Population Abstract #4536 Poster Presentation Monday, December 11 6:00 – 8:00 PM PT Scemblix® (asciminib) With up to 8 Years of Therapy, Asciminib (ASC) Monotherapy Demonstrated Continued Favorable Efficacy, Safety, and Tolerability in Patients (Pts) with Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP) without the T315I Mutation: Final Results from the Phase 1 X2101 Study Abstract #450 Oral Presentation Sunday, December 10 10:45 AM PT Sickle Cell Disease Targeted Degradation of the Wiz Transcription Factor for Gamma Globin De-Repression Abstract #2 Plenary Scientific Session Sunday, December 10 2:00 – 4:00 PM PT Kymriah® (tisagenlecleucel) Clinical Outcomes of Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 Elara 3-Year Follow-up Abstract #601 Oral Presentation Sunday, December 10 4:30 PM PT Jakavi® (ruxolitinib) Ruxolitinib in Patients With Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of Efficacy and Safety From the Phase III REACH3 study Abstract #654 Oral Presentation Sunday, December 10 5:45 PM PT Immune Thrombocytopenia (ITP) The lack of tolerable treatment options that can induce durable responses without fear of relapse after discontinuation represents a significant unmet need for patients (pts) with immune thrombocytopenia (ITP): Results from the ITP world impact survey (I-WISh) 2.0 Abstract #1212 Poster Presentation Saturday, December 9 5:30 – 7:30 PM PT Product Information For full prescribing information, including approved indications and important safety information about marketed products, please visit . Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at and connect with us on LinkedIn, Facebook, X/Twitter and Instagram. # # # * Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals. Novartis Media Relations E-mail: media.relations@novartis.com Central North America Richard Jarvis +41 79 584 2326 Julie Masow +1 862 579 8456 Anja von Treskow Anna Schäfers +41 79 392 9697 +41 79 801 7267 Michael Meo Marlena Abdinoor +1 862 274 5414 +1 617 335 9525 Switzerland Satoshi Sugimoto +41 79 619 2035 Novartis Investor Relations Central investor relations line: +41 61 324 7944 E-mail: investor.relations@novartis.com Central North America Samir Shah +41 61 324 7944 Sloan Simpson +1 862 345 4440 Nicole Zinsli-Somm +41 61 324 3809 Parag Mahanti +1 973 876 4912 Isabella Zinck +41 61 324 7188 Jonathan Graham +1 201 602 9921 Imke Kappes +41 61 324 82 69 Zain Iqbal +41 61 324 03 90

Clinical ResultPhase 3ASHPhase 1Phase 2

02 Oct 2023

·www.fiercebiotech.com

Analyst applauds Novartis’ ‘faultless’ iptacopan performance in phase 3 kidney trial

Financial analyst group ODDO BHF has called iptacopan's early performance in a phase 3 kidney disorder trial “faultless." Novartis’ investigational oral factor B inhibitor has hit its early target in a phase 3 kidney disorder trial, a success that has the pharma readying to submit a request for fast-track FDA approval next year. The 9-month data comes from the Swiss pharma’s APPLAUSE-IgAN study, with topline results expected in 2025. The double-blind, placebo-controlled trial is designed to measure the efficacy and safety of twice-daily oral iptacopan among 470 adults with IgA nephropathy (IgAN), a chronic kidney disease also known as Berger’s disease. The therapy hit the study’s intermediary primary end point, demonstrating statistically significant superiority compared to placebo in proteinuria reduction, according to Novartis, though no figures were provided. The study continues to assess the pill’s ability to slow IgAN progression by measuring estimated glomerular filtration rate slope over two years. The data is a homerun for Novartis, according to financial analyst group ODDO BHF, who dubbed iptacopan’s performance “faultless” in a Oct. 2 report. Beyond the potential for becoming the first oral monotherapy for IgAN patients, iptacopan could also become the first targeted IgAN treatment that slows or prevents progression to kidney failure by activating the complement system, according to Novartis. APPLAUSE-IgAN demonstrated a safety profile consistent with previously reported data from two phase 3 studies for paroxysmal nocturnal hemoglobinuria (PNH). Based on those trials, Novartis has submitted iptacopan to regulators in the rare disease indication and expects a response in 2024. If approved in PNH, Novartis will give AstraZeneca’s rare disease unit Alexion a run for its money, going up against complement inhibitors Soliris and Ultomiris. Previously, iptacopan out-performed Soliris in a head-to-head PNH trial. Iptacopan has “pipeline in a pill” potential, according to ODDO BHF analysts. The pill is also being developed to treat several other renal and hematological diseases that currently lack available treatment or unsatisfactory treatments. ODDO BHF anticipates an initial iptacopan launch in 2024 and peak sales of more than $3 billion when considering all indications.

Phase 3Clinical Result

100 Deals associated with PF-9601N

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Discovery	ES	Universitat Autònoma de Barcelona	-

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