Donald Gehlert, Ph.D.

The past two days have witnessed two Nobel Prize awards to machine learning and artificial intelligence. Kudos to Geoff Hinton, John Hopfield, David Baker, Demis Hassabis and John Jumper for their amazing contributions. In chemistry, the story of AI/ML goes back to Corwin Hansch and Toshio Fujita (1962), who started the field of QSAR. Fun fact (Alicia Higueruelo and Jordi Mestres can confirm): At #EuroQSAR in Barcelona, on September 27, I openly stated that Jumper & Hassabis are strong contenders for the Nobel prize. At least one prediction from that conference proved to be accurate. Back to this Editorial (once again, thank you Craig Lindsley, Ph.D., FRSC, FASPET, FAAS, FNAI). I am glad it got published "as is", with very minor modifications from May 2003. Indeed, the text and references have not been modified since. To paraphrase one of David Weininger's friends, Douglas Adams, "[chemical] Space is big. Really big. You just won't believe how vastly, hugely, mind-bogglingly big it is. I mean, you may think it's a long way down the road to the chemist's, but that's just peanuts to space" . Chemists will need computers & AI to navigate that really big chemical space. Note to non-UK English speakers: chemist == pharmacist in this instance.

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As an extremely complex disease, researchers must try to treat ALS from many different angles, addressing many different potential drug targets. What follows is a basic guide to some of the more common types of drugs in the ALS pipeline today. https://lnkd.in/gqpckvC9

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Acurx Pharmaceuticals Announces Presentation of Ibezapolstat Phase 2 Clinical Trial Results for CDI at Scientific Conference   • Additional analyses of clinical and microbiological data from the Phase 2b segment show favorable gut microbiome changes including increased relative proportion of Actinobacteria in ibezapolstat-treated patients with C. difficile Infection (CDI) • Results consistent with those shown in earlier human volunteer studies and Phase 2a studies • Preservation and increased concentrations of beneficial Firmicute (Bacilotta) phylum known to be involved in bile acid homeostasis and short chain fatty acid metabolism was demonstrated  • Actinobacteria and Bacteroides preservation also confirmed using quantitative analysis   https://lnkd.in/eseFt8GZ   #nasdaq #acxp #antibiotics #acurx Acurx Pharmaceuticals, Inc. (Nasdaq: ACXP) David Luci

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Christian Ramirez Amarilla now at #BITS2024 about how inhibiting METTL3, an important RNA methyltransferase, affects RNA structure, adenosine-to-inosine (A-to-I) editing, and the immune response in leukemia models, providing new insights into potential therapeutic approaches for leukemia. #Bioinformatics #LeukemiaResearch #BITS2024

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Among the multitude of single-cell technologies, which one should you choose? A comprehensive benchmarking study by a team from Genentech can help make that choice easier. They used PBMCs to evaluate the performance of droplet, microwell, and combinatorial indexing-based methods from various companies that offer single-cell technology. 07/08/24 edit: please see response from Singleron by Harlin Jhyont below in the comment. “This study provides a comprehensive and systematic evaluation of commercially-available scRNA-seq kits and sheds light on the various strengths and weaknesses of each kit with respect to time, cost, functionality and performance, which should facilitate an optimal and informed selection of a suitable scRNA-seq approach.” “Overall, 10x FRP exhibited the highest ranked performance followed by 10x 3’, BD, Scale, 10x 5’ / Parse (tie), Fluent, Honeycomb, and Scipio. Singleron was excluded from the cell-based comparisons due to unreliable cell calling; however, based on UMI count, gene count, and usable mapped reads, it exhibited the lowest performance at the library level.” https://lnkd.in/eTk3jYVQ #singlecell #science

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Dr. Nina E. Weisser, Director of Preclinical, Multispecific Antibody Therapeutics, recently authored an article published in Drug Target Review discussing the development of trispecific T cell engagers (TriTCEs) with integrated CD28 costimulation. TriTCEs are designed to address the limitations of conventional bispecific TCEs in treating solid tumors by providing balanced T cell activation, leading to potentially more sustainable anti-tumor responses. This innovative approach could significantly advance immunotherapy for patients with difficult-to-treat solid tumors. Access the article: https://lnkd.in/ewRJvPA9

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“Micro-doses of Mitochondrial Uncoupler MP101 in hSOD1 G93A Provides the First Ever Small Molecule with Functional Recovery from Paralysis and Hints that ALS is a Solvable Problem” is the topic of my talk one month from today, at ALS ONE "Industry Day" Nov 14, 11:40 – 12:00pm. Please join me for a Mitochon Pharmaceuticals, Inc., brief overview of both our "disruptive" preclinical work, sALS clinical study ongoing now in Europe, and plans for future studies in USA/Europe. https://lnkd.in/eeQNWQAk #ALS #mitochondria

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My second post this week on the benefit of using recombinant alpaca antibodies is one that touches on an all too familiar topic Cancer. Unfortunately Cancer impacts everyone either directly or indirectly in this world and it has sadly taken a loved one away from the majority of us too soon. Cancer is a complex disease with many different varieties of it and due to such variation clinicians need an array of different tools/strategies to treat and cure the different varieties of Cancer. Scientists around the world who are alot smarter than me have been working hard in their laboratories trying to discover new ways to defeat cancer. Did you know, that these very smart scientists have now discovered that recombinant alpaca antibodies are incredibly useful tools when developing new treatments and cures for Cancer. I recently read the paper below which shows that when you combine recombinant alpaca antibodies with your own immune cells it can result in the destruction of tumors which is really cool and useful in the fight against Cancer. Indeed the very smart scientists found that recombinant alpaca antibodies were better and easier to use than antibodies from other species. This form of treatment approach that the clever scientists used is called CAR-T cell therapy, a rapidly growing area in biopharma and one which Afrobodies is developing recombinant alpaca antibodies for. If you know of anyone working with CAR-T cell therapy please share the research paper below with them so they can see the benefit of working with the coolest molecules in science, recombinant alpaca antibodies or what we Afrobodies more affectionately call Afrobods and the rest of the world calls nanobodies. Our one liner at Afrobodies is "everyone needs an Afrobod" :) Afrobodies September "back to school" offer now allows you to start working with recombinant alpaca antibodies in your own lab for an affordable price. If you are in the UK and want to access Afrobodies incredibly well priced "back to school offer" for nanobody discovery contact our distributor there 2BScientific Ltd. Maybe you can discover the next CAR-T cell therapy for a currently incurable Cancer. Together we will defeat Cancer. Who would have thought that the defeat of cancer would be a team effort between two legged humans and super cute but immensely clever 4 legged alpacas! :) #vhh #alpaca #antibodies #Cancer #therapeutics #singledomain #recombinant #afrobodies https://lnkd.in/d68DKXPQ

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Bristol Myers Squibb has queued a Phase 1 study of Orum Therapeutics’ ORM-6151 (BMS-986497), a first-in-class, anti-CD33 antibody-enabled GSPT1 degrader for the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndromes. The study will enroll an estimated 35 patients and is due to start in late May 2024. Orum Therapeutics has developed a new class of ADC payloads, called neoDegraders, to specifically degrade intracellular target proteins within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, neoDegraders are designed to be delivered specifically to cancer cells and degrade the intracellular target protein and cause tumor cell death. https://lnkd.in/edTcDRFj

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SDBN Feed: Candid Therapeutics unwraps three new collaborations to discover and develop T-cell engager antibodies https://lnkd.in/g4rKJTSk Candid Therapeutics, a new San Diego biotech bent on becoming a leader in the emerging T-cell engager space, has unwrapped three new research collaborations focusing on autoimmune diseases. Candid will partner with EpimAb Biotherapeutics, Nona [...]

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What does computation-driven drug discovery look like from a peptide's perspective? Hint: unnatural amino acids are necessary. A 2 nm view of Atommap.

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Highly specific and potent #TCR s against self-antigens are cleared due to central tolerance and cannot be recovered as #therapeutic drugs, right? In the current edition of Immunity, Steve Elledge from Harvard Medical School present a strategy to raise TCRs against mutated self-antigens (synthetic #neoepitope) and #screening for TCRs that recognise WT antigen after some kind of affinity maturation. Validity of the approach is demonstrated on #HLA A*02:01-restricted ALLSGVRQV from tyrosine hydroxylase, an antigen highly expressed in neuroblastoma. While resulting TCRs may indeed present #tumor-targeting reagents and the success of the screening seems to work, a look into Alithea Bio HLA-Compass identifies ALLSGVRQV not as an abundant self-antigen, but a rather tissue-restricted antigen that may have slightly different effects on availability of endogenous TCRs than other very abundant antigens. The very specific expression in adrenal glands warrants studying the medical implications of this obvious on-target toxicity. Is it manageable? My other immediate thought was if such TCRs against self-antigens could be used in #autoimmunity guiding anti-inflammatory cells to inflamed tissues? Picture from HLA-Compass in the comments. #precisionmedicine #cancer #ACT #Tcells #cellandgenetherapy #immunopeptidomics

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InnaRx to Present Positive Phase 2 Data on MY008211A in Poster Presentation at the 66th ASH Annual Meeting & Exposition Gaithersburg, M.D., Oct 25, 2024— InnaRx, a clinical-stage biotechnology company specializing in oral modulators targeting innate immunity pathways, today announced an upcoming poster presentation at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 7–10, 2024, in San Diego, CA. This poster presentation will feature findings from a Phase 2 dose-finding study of MY008211A, an investigational oral complement factor B inhibitor, in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) experiencing active hemolysis. A Phase 2 Dose-Finding Trial of MY008211A in Complement Inhibitor–Naive Patients with Paroxysmal Nocturnal Hemoglobinuria and Signs of Active Hemolysis (Abstract #2701) Session Name: 508. Bone Marrow Failure: Acquired: Poster II Session Date: Sunday, December 8, 2024 Presentation Time: 6:00 PM - 8:00 PM PT Location: San Diego Convention Center, Halls G-H This Phase 2, multicenter, open-label study evaluated three dosing regimens of MY008211A in complement inhibitor–naive patients with PNH, a life-threatening blood disorder characterized by red blood cell destruction, blood clots, and bone marrow failure. Over the 12-week study period, all 34 patients achieved the primary endpoint—an increase in hemoglobin (Hb) concentration of ≥20 g/L from baseline—while also demonstrating significant control over hemolysis and improvements in patient-reported fatigue levels. MY008211A was well tolerated across all dosing regimens, with no treatment-related serious adverse events and only mild to moderate side effects, supporting its potential as a new treatment option for PNH. "We are excited to share these promising results with the hematology community at ASH," said Wilson Wang, VP of corporate development. "The success in our proof-of-concept study in PNH demonstrated MY008’s broad potential as a proven innate immunity modulator for complement-mediated autoimmune diseases.” InnaRx invites attendees at the ASH Annual Meeting to visit the poster session to discuss these findings and learn more about MY008’s development. About InnaRx InnaRx is a clinical-stage biotechnology company developing best-in-class oral modulators targeting innate immunity pathways for immunological and inflammatory (I&I) diseases. InnaRx’s innovative approach to immune modulation offers new options for managing complex and rare immunological conditions, with proof-of-concept demonstrated in clinical studies.

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𝗔𝗥𝗖𝗛, 𝗙-𝗣𝗿𝗶𝗺𝗲 𝗮𝗻𝗱 𝗠𝘂𝗯𝗮𝗱𝗮𝗹𝗮 𝗽𝘂𝗺𝗽 $𝟮𝟬𝟬𝗠 𝗶𝗻𝘁𝗼 𝗳𝗼𝗿𝗺𝗲𝗿 𝗗𝗲𝗻𝗮𝗹𝗶 𝗽𝗿𝗼𝗴𝗿𝗮𝗺𝘀 A new startup has emerged with $200 million and access to multiple preclinical drug candidates from neuroscience drugmaker Denali Therapeutics. Tenvie Therapeutics,Tony Estrada https://lnkd.in/dKN6kQeH

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CMG publishes new ACMG Therapeutics Bulletin: “Trofinetide approved for children and adults with Rett syndrome (RTT)” in GIM Open, the College’s gold open access journal: https://bit.ly/3zOe6iI #Therapeutics #medicalgenetics #GIMOpen #RettSyndrome #MedicalEducation Rett syndrome (RTT) affects 1 in 10,000 to 23,000 females globally, making it one of the most common genetic causes of intellectual and developmental impairment in females. Trofinetide improved neuronal and synaptic function in study participants with RTT. Participants showed improvement in various behavioral, visual & communication aspects. Clinicians should plan for the most frequent side effects of trofinetide (diarrhea & vomiting) should they occur.

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11 Antibody & 4 VHH full-platform transfers (Bayer, Bonum, Sanofi, Scholar Rock, Servier-Symphogen, UCB, EpiBiologics and others undisclosed). Now able to disclose Abbvie. Our libraries are popular. Jeff's talk explains why: high affinities, excellent developability, great diversities.

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For anyone building diagnostics: Very cool approach to gain valuable insights into FDA decision summaries. Brendan O'Leary scraped the FDA’s decision summaries and provided some simple R code for anyone to get up and running in no time to prod and probe those summaries. Very nice work!

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