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Small Molecule Highlights #03 – December 2022

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This month’s blog features several recently reported small molecules with interesting structural motifs, including tetrahydroquinolines, spiroazetidines, diheterocyclic pyrroles, pyridinones, as well as covalent acrylamide electrophiles. In addition, these analogs were designed to bind a diverse list of molecular targets, such as SGRM, KRAS, CDK, NNRT, EGFR, ProRS, and SARS-CoV2.

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Small Molecule Highlights #03 – December 2022


Dalriada Small Molecule Highlights 03 - B53

B53: Through an extensive SAR of 62 sulfonamide tetrahydroquinolines, B53 was identified as a selective glucocorticoid receptor modulator (SGRM) for utility in immunology. It was found to have potent transrepression (IC50 NF-κB = 9 nM) with no transactivation. The compound also reduces the expression of several inflammatory biomarkers such as IL-6, IL-1β, and TNF- α. In an in vivo DNCB-induced atopic dermatitis model, efficacy was observed at 20 mg/kg (P.O.)

Reference: https://doi.org/10.1021/acs.jmedchem.2c01082


Dalriada Small Molecule Highlights 03 - TB-25

TB-25: Using a ring-fusion strategy towards a colchicine-binding site inhibiting pharmacophore, Imidazo[1,2-a]pyrazine TB-25 was identified as a tubulin small molecule inhibitor. Cytotoxicity was observed against HePG-2, HCT-116, A459, and MDA-MB-231 cells, with IC50 values of 146, 23, 154, and 74 nM, respectively. The induction of apoptosis in HCT-116 (colon cancer) cells was studied, with 50.1% induction at 120 nM. Cell cycle arrest (at G2/M phase) was also observed (79.6%, at 120 nM). In a wound-healing assay studying the relation between cell migration, and tubulin inhibition, 60.5% inhibition was observed at 80 nM of inhibitor.

Reference: https://doi.org/10.1016/j.bmc.2022.117098

Compound 15B

Dalriada Small Molecule Highlights 03 - Compound 15B
Compound 15B

Compound 15B: Structurally derived from Spautin-1, Compound 15B is an EGFR inhibitor, targeting the mutant protein isoform (Ex19Del, L858R/T790M). From an original micromolar hit compound (5 μM potency) to Compound 15B (NSCLC PC-9 IC50 = 4 nM). Synthesis of the central quinazoline core involved formamide coupling via the use of 2-carboxyanilines. Upon co-incubation with established covalent EGFRi Afatinib, a 2x improvement in potency was observed (with the authors indicating a possible additive effect).

Reference: https://doi.org/10.1016/j.bmcl.2022.129066


Dalriada Small Molecule Highlights 03 - B2

B2: Through lead optimization of a previously identified CDK7 targeting hit molecule (THZ1, PDB 6XD3), B2 was designed as a covalent CDK inhibitor, for utility in autosomal dominant polycystic kidney disease (AD-PKD). Potency was observed against CDK7 (IC50 = 4 nM), with less activity against other CDK isoforms (CDK1, 2, 3, 5, 6, 9, 12 IC50 = 0.5 – 10 μM). At 1 μM, a kinome screen revealed off targets as GSK3β, AMPKα1, TAK1, PKCθ, JAK2. Efficacy was observed in a MDCK cyst model/ADPKD mouse model (at 5 mg/kg) (S.C.).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01334


Dalriada Small Molecule Highlights 03 - JDQ443

JDQ443: As a stable atropisomer (predicted interconversion barrier, ΔErot = 35.9 kcal mol-1) with a unique pyrazole core, JDQ443 was developed as a covalent KRASG12C inhibitor through a structure-based drug design strategy, coupled with de nova HitID, and electrophile reactivity optimization (via a spiro-azetidine linker). Activity against pERK was found (IC50 = 20 nM in NCI-H358mut), with a kinact/Ki value of 141 mM-1s-1. A co-crystal structure (7R0M) revealed the presence of novel interactions beyond canonical His95. Efficacy was demonstrated in a MIA Paca-2 tumor model (-87% MTV, day 20), at 30 mg/kg (p.o./q.d.).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01438

Compound 9Q

Dalriada Small Molecule Highlights 03 - Compound 9Q
Compound 9Q

Compound 9Q: As a N-pyridinylpyrimid-2-amine, this small molecule was identified as a dual inhibitor of CDK7/9 with noticeable % inhibition at 1 μM of 87, and 90%, respectively. This activity translated into an apparent Ki (CDK7H/CDK9T1) of 55, and 38 nM with [ATP] held at the enzyme Michaelis constant (Km). Broad cytotoxicity was observed in various cell lines, including MCF-7 (breast cancer), A2780 (ovarian cancer), H460 (non-small cell lung cancer) and MV4-11 (acute myeloid leukemia), with IC50 ranges between 150-550 nM. The induction of apoptosis was also established in MV4-11 cells, using FACS Annexin V/PI based protocols.

Reference: https://doi.org/10.1002/cmdc.202200582

Compound 1F

Dalriada Small Molecule Highlights 03 - Compound 1F
Compound 1F

Compound 1F: This small molecule, with a bis-furyl-pyrrolo[3,4-b]pyridin5-one core was reported as a SARS-CoV2 inhibitor. Interestingly, the design/synthesis of this molecule (and related analogs) involved the use of a one-pot 3-component Ugi-Zhu reaction (UZ-3CR), in the presence of a Yb(OTf)3 catalyst, which generally involves the reaction of aldehydes, amines, and isocyanide motifs. The % inhibition of SARS-CoV2 infection Vero-E6 was found to be 31.9, and 15 % in EC1, EC2, respectively. The inhibitor was found to display both prophylactic, and therapeutic benefits. In a receptor-ligand docking study against MPro, NSP3, and the spike-glycoprotein, virtual binding scores of -5.71, -4.72, and -4.49 kcal mol-1 were observed, respectively.

Reference: https://doi.org/10.1039/D2MD00350C

Compound 3

Dalriada Small Molecule Highlights 03 - Compound 3
Compound 3

Compound 3: This quinazoline molecule was identified as a Staphylococcus aureus (gram-positive bacteria) prolyl-tRNA synthetase (SaProRS) inhibitor. Interestingly, a co-crystal of the SaProRS: 3:AMPPNP ternary complex (PDB 5ZNK) suggested an ATP-aided mechanism of action. This was further supported by determining the Kd in the presence/absence of ATP, with values of 30 nM, and 376 μM (represents a ~104-fold increase). MIC values in E. coli (GPB)/MRSA252 (GNB) were found to be 1 μg/mL, with IC50 in SaProRS of 150 nM. Fluorescence-based thermal shift analysis against both SaProRS/ EcProRS found ΔTm (oC) values of 10.2, and 20.4 oC, respectively.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01496

Compound 36A

Dalriada Small Molecule Highlights 03 - Compound 36A
Compound 36A

Compound 36A: Using a structure-based drug design, and molecular docking strategy, 36A was identified as a non-nucleoside reverse transcriptase (NNRT) inhibitor, for anti-viral utility against HIV-1. Broad activity was observed against wild-type HIV-1 (EC50 = 2.2 nM), as well as several relevant mutants: L1001, K103N (EC50 = 3.0, 2.8 nM). Against RES056, an EC50 value of 53.3 nM was observed. Using SPR analysis, an HIV-1 Kd was found as 2.50 μM, which is comparable to clinical standard HIV-1 medicine Etravirine. Several pharmacokinetic parameters of the hydrochloride salt (36A.HCl) were also determined at 10 mg/kg (P.O.), including T1/2 = 5.12 hrs, Tmax = 0.25 hrs, and F (%) at 12%.

Reference: https://doi.org/10.1021/acs.jmedchem.2c00576

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Adam Davenport, PhD

Chief R&D Officer

Adam is Dalriada’s Chief R&D Officer. A seasoned drug hunter and innovator, he brings over 22 years of hands-on life science and partnership organization experience, having contributed to drug candidates and clinical assets through both governance and leadership roles.

Prior to Dalriada, Adam’s outstanding career was spent at Evotec, then Oxford Asymmetry International, which he joined in 2001. There, he gained extensive experience from Hit ID through to IND, across diverse modalities, target classes (GPCRs, ion-channels, PPIs, CNS, kinases, enzymes) and therapeutic areas (pain, inflammation, cognition, metabolic, Women’s Health and respiratory).

As a Project Leader, Adam has progressed multiple projects through Discovery into Clinical evaluation and is lead inventor of P2X3R antagonists Eliapixant and Filopixant, achieving Phase 2a PoCs in Persistent Chronic Cough (PCC), and Bradykinin B1R antagonist Fulimetibant, undergoing a Phase 2a study to treat diabetic neuropathic pain (DNP).

Adam’s promotion to VP Medicinal Chemistry saw him take on scientific and strategic portfolio responsibilities as well as operational duties in Abingdon, UK. Progression through Senior to Executive VP expanded Adam’s leadership and strategic influence on the organisation, where he established and led as Head of Global Molecular Discovery, a multi-modality data-driven Design and Synthesis function based in the UK, FR, IT and US.

Passionate about science and communication, Adam has authored over 55 patents, publications and external presentations and was co-recipient of the Bayer Healthcare Drug Discovery Award for Collaborative Innovation in 2017.

Adam holds a B.Sc. Honours degree in Chemistry and a PhD in Organometallic Chemistry from the University of Leicester, UK.

Frosty Loechel, PhD

SVP Biology

Frosty is Dalriada’s Head of Biology, responsible for the scientific strategy of the discovery program in biology and a key contributor to the continuous evaluation of our scientific capabilities, operations, and infrastructure. He brings 20 years’ academic experience and 25 years working in pharma, biotech, and CROs.

Before joining Dalriada, Frosty gained exceptional experience in discovery programs at Evotec. First as a VP, Metabolic diseases, he built up a large department running iPSC work, in vitro pharmacology, advanced cellular platforms, transcriptomics, imaging, and data science. Then, as SVP, Therapeutic Area Lead and Scientific Director, he led on new collaborative drug discovery agreements with pharma/biotech partners and on the strategy of project portfolio in major multi-target collaborations.

Prior experience includes work at Zealand Pharma, where he focused on peptide drugs for a portfolio of diabetes and obesity projects. His earlier career was spent at Lundbeck, Thermo Fisher, Neurosearch and BioImage, where he gained a strong background in a broad spectrum of scientific areas.

Frosty has been involved in hundreds of drug discovery projects and gained a wealth of experience across multiple areas and therapeutic modalities including CNS and metabolic diseases. His expertise spans all stages of drug discovery, from target identification and validation to Hit-to-Lead and Lead Optimization, and nomination of preclinical candidates. He is familiar with multiple modalities, from small molecules, to peptides, to biologics, and brings extensive experience with target classes such as GPCRs, kinases, transporters, ion channels and proteases.

Frosty has a B.A. in Biochemistry from the University of Kansas, and a Ph.D. from the Faculty of Health Sciences of the University of Copenhagen. He is a Danish citizen and is fluent in English, Danish, and Italian.

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Brian Sequeira

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Brian completed his BSc degree in Computer Science from the University of Toronto and certified as a Project Management trainer with Kepner Tregoe.

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Harpreet Kaur, PhD

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Mohammad Eram, PhD

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Prior to joining Dalriada, Mohammad worked on early stage hit discovery projects at the Structural Genomics Consortium in Toronto, including projects in collaboration with Bayer, Takeda, Eli Lilly, and Merck. His work at SGC focused on biochemical and biophysical methods with applications to high-throughput and fragment-based drug discovery.

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Jeff O’Meara, MSc

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Previously, Jeff spent 8 years as an integral part of the Ontario Institute for Cancer Research’s Drug Discovery team where he drove hit to lead and lead optimization projects of which two were eventually partnered with pharma in deals totaling > $2B. Jeff also trained for 17 years as a medicinal chemist and project team leader at Boehringer Ingelheim Canada Ltd. where he helped discover several novel antivirals that progressed to clinical trials. He has published more than 50 papers and patents in the fields of medicinal chemistry and drug discovery and in 2010 was the recipient of the American Chemical Society’s TAOC award.

Jeff has an M.Sc. in organic chemistry from University of Ottawa.

Tom Coulter

Tom Coulter, PhD

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Rav Kumar

Rav Kumar, PhD

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Dr. Rav Kumar is Chief Strategy Officer at Dalriada. He spent 25 years with GlaxoSmithKline (GSK) in the UK, France and Canada at vice-president level leading pharmaceutical R&D and business development. Key areas of expertise include formulation development, regulatory submissions, manufacturing and GMP audits. He has been involved with development of numerous medicines and vaccines plus many successful business change initiatives.

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Dr. Kumar also serves as Director of The Centre for Medicinal Chemistry and an Assistant Professor at University of Toronto. He has a Pharmacy Degree and completed a PhD in Novel Drug Delivery at University of Bath in the UK.

Charlie Younger

Charlie Younger, PhD

Chief Operating Officer

Charlie joined Dalriada in 2020 as Chief Operating Officer, bringing over 25 years of pharma/biopharma experience. Charlie has a proven track record of leading organizations through rapid growth and transformations.

Charlie started his career as an Analytical Scientist at Glaxo and has taken on progressive leadership roles in pharma/biopharma. Charlie has worked with leading private and public pharma/biopharma organizations including leadership roles at CROs such as Patheon and Therapure Biopharma. He has also served as COO in both public and private organizations.

Driven by a personal passion to grow R&D in Canada, he has been a contributing member on multiple SR&ED tasks forces and executive roles in training organizations.

More recently, Charlie runs his own professional services business since 2016, helping companies grow and/or streamline operations for start-ups through to $B+ multinationals. He completed an HBSc in Chemistry at Western University (Canada) and a PhD in Organic Chemistry at McMaster University (Canada).

Patrick Gunning

Patrick Gunning, PhD

Co-founder & CSO

Patrick is a Professor of Chemistry at the University of Toronto, Canada Research Chair in Medicinal Chemistry, and Founder and Chief Scientific Director of the Centre for Medicinal Chemistry (UofT). Patrick obtained his PhD at the University of Glasgow in 2005 under the supervision of Profs. Robert Peacock and Andrew C. Benniston, and conducted post-doctoral studies at Yale University with Prof Andrew Hamilton.

Patrick’s research has focused on developing inhibitors of numerous protein classes, including transcription factors, kinases, and epigenetic targets, using novel covalent therapeutics and monovalent protein degraders. Patrick has published ~120 research papers, is a Fellow of the Royal Society of Chemistry, won 20 research awards including Canada’s Top 40 under 40, the 2010 Boehringer Ingelheim Young Investigator Award, the 2012 RSC MedChemComm Emerging Investigator Lectureship by the Royal Society for Chemistry, Rose Winer Levin Lectureship at the Dana-Farber Cancer Institute (2015), and the 2016 Canadian Society for Chemistry’s Bernard Belleau award.

Patrick, the co-founder and CSO of Dalriada Drug Discovery, has founded three other biotech companies with over $34M in funding, including Janpix Inc, now a Centessa Pharmaceuticals’ company, Dunad Therapeutics, and Dalriada Therapeutics.

Diana Kraskouskaya

Diana Kraskouskaya, PhD

Co-founder & CEO

Diana completed Honors BSc Degree in Molecular Biology and PhD in Medicinal Chemistry from the University of Toronto, and is a co-founder of two other biotechs, which have raised > $10 M in VC funding.

During her time in academia and biotech, Diana worked on diverse small molecule programs across protein-protein interactions, epigenetics, GPCRs, covalent inhibitors, and is an inventor on several patents.

As a co-founder and Chief Executive Officer of Dalriada, Diana brings to Dalriada years of leadership and hands-on cross-disciplinary biotech and drug discovery experience spanning areas of company building, scientific & IP program strategy, and operations. ​

Following completion of her PhD, Diana took appointment as a research manager of the Centre for Medicinal Chemistry, where she was involved in multiple drug discovery programs and provided oversight over the build-out of the >$100 M integrated drug discovery infrastructure at the University of Toronto. Diana co-founded and led two other biotechs, Dunad Therapeutics and Dalriada Therapeutics. In this process she recognized the shortcomings of the existing options for outsourcing innovative science, which led to the creation of Dalriada Drug Discovery’s Turn-Key™ Model. With this new model and under Diana’s leadership the company has grown to over 60 people within 3 years. ​

Diana is the recipient of several entrepreneurship awards, including RBC Prize for Innovation & Entrepreneurship and the 2018 MNP Future Leaders awards.

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