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Small Molecule Highlights #06 – January 2023

In the following list of small molecule highlights, we summarize an international list of structurally novel reports out of Novartis (Switzerland), Pfizer (USA), and Merck (USA), in addition to academic institutions including CAMS/SJTU/UESTU/SU/SPU (China), OICR/PMCC (Canada), IRBM (Italy), and the University of Nottingham (UK). The molecules presented bind a varied list of drug targets, including JAK kinases, RORC2, GCS, NSD2, EZH2, BCL6, and sEH proteins (via standard or covalent mechanisms). In addition, while most entries are canonical orthosteric binders, select examples do include allosteric inhibitors, as well as partial agonists, antagonists, etc. Finally, a few examples also utilize a topical route of administration, with limited systemic potency – which introduces the concept of a soft drug.

Small Molecule Highlights 06 – January 2023

CEE321

CEE321
CEE321

CEE321: This molecule was disclosed by Novartis, as a panJAKi (JAK1-3, TYK2) with therapeutic utility as an anti-inflammatory agent against atopic dermatitis (also known as Eczema). Interestingly, this small molecule observes limited systemic potency (in the blood, in vivo), while displaying good efficacy as a topical therapy – referred to as a soft drug. Enzymatic inhibitory values against JAK1, JAK2, JAK3, and TYK2 were reported as 50, 48, 59, and 50 nM, respectively. Cellular activity against IL15 (JAK1/JAK3), and IFNα (JAK1/TYK2) were found as 54, and 85 nM, respectively. Intrinsic clearance in rats via liver microsomes was found to be 204 mL/min g, while hepatocytes displayed a lower value of 94 mL/min g. Overall, a half-life of 0.5 hrs was observed. As a cream (used at 0.2% CEE321), this molecule displayed topical efficacy in the inhibition of IL4/IL13 mediated phosphorylation of STAT6, as well as MMP12 gene expression.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01977

 

Compound 14

Compound 14
Compound 14

Compound 14: As an inverse agonist of retinoic acid receptor-related orphan receptor C2 (RORC2), this macrocycle out of Pfizer, has been reported as an anti-inflammatory topical therapy. The use of a macrocycle was based on a structure-based drug design (SBDD) strategy via co-crystal analysis (PDB 8FAV, 8FB1, 8FB2). In vitro TR-FRET based RORC2 IC50 = 9.3 nM, while a cellular IL-17 IC50 = 28 nM was found. Synthetically, ring-closure involved an Olefin metathesis step (using Grubb’s 2nd generation catalyst), after which the alkene was reduced using hydrogenation (in the presence of PtO2). Over a period of 14 hrs, topical in vitro permeation of compound 14 increases to 400 ng/cm2. In addition, 24 hrs post-application, ~90 μg/g is delivered into the epidermis, while ~25 μg/g to the dermis.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00500

 

Compound 16

Compound 16
Compound 16

Compound 16: This bicycle pyrazole urea by Merck was reported as a low dose, orally-bioavailable, central nervous system (CNS) penetrant inhibitor of Glucosylceramide Synthase (GCS), as a medicinal agent against Parkinson’s Disease (PD). Compound 16 was discovered through a high-throughput screen (HTS), following by computational analysis, and quantitative SAR (QSAR) models. Against GCS, a biochemical IC50 of 1.8 nM was found, while 5-HT3 IC50 of 1970 nM was observed. In addition, little-to-no activity was observed against the relevant CYP enzymes (IC50 > 50 μM). In rats, in vivo pharmacokinetic analysis revealed a mean residence time (MRT) of 5.3 hrs, % F of 95%, and a VLE of 7.5. In vivo efficacy was also observed in a relevant mouse models, while ex vivo efficacy was reported in iPSC neuronal models.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00441

 

Compound 15A

Compound 15A
Compound 15A

Compound 15A: The following small molecule with a structurally unique bicyclo[1.1.1]pentane linker was reported as a histone lysine methyltransferase NSD2 inhibitor. Optimizations involved the derivatization of an earlier quinoline-5,8-dione HTS hit (known as DA3003-1). Interestingly, while the MOA has not been disclosed, the molecule does contain a Cys reactive 2-butyneamide (as seen in the well-established covalent BTKi Acalabrutinib, CalquenceTM) which may suggest a prospective covalent mechanism. In vitro, NSD2 IC50 of 230 nM, while cellular activity against multiple myeloma (MM) line KMS-11 was found to display an IC50 of 270 nM. At 3.0 mg/kg (p.o.), a T1/2 of 6.71 hrs was reported. Finally, in vivo efficacy was established in KMS-11 MM tumour xenografts (in SCID mice), at 150 mg/kg (p.o.) with a TGI of 58.6%.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01920

 

SKLB-03220

SKLB-03220
SKLB-03220

SKLB-03220: Enhancer of zeste homologue 2 (EZH2) represents the enzymatic catalytic subunit of PCR2, which plays diverse roles in histone post-translational modifications (PTMs), and the incidence/ progression of human cancers. SKLB-03220 has been reported as a covalent EZH2 inhibitor, with utility as a potential anti-cancer agent. Inhibitor design followed an SBDD strategy (via co-crystal structure analysis, PDB 5WG6). Against EZH2WT, an IC50 of 1.72 nM was reported, while against EZH2Mut IC50 values < 10 nM were found. As a covalent inhibitor, target engagement is predicted to go through a standard 1,4-conjugate addition via the acrylamide electrophile (via Cys663). Covalent target engagement was validated using koff analysis, intact-mass analysis, and cellular washout experiments. In a PA-1 xenograft tumour model (using Balb-C mice), in vivo efficacy was found, at 150 mg/kg (p.o.), with a TGI of 78.2%.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01370

 

OICR12694

OICR12694
OICR12694

OICR12694: Through extensive structural optimization of a virtual screen weakly-binding hit compound (SPR KD = 282 μM), OICR12694 was developed as a potent inhibitor of transcriptional repressor B cell lymphoma 6 (BCL6). In vitro studies found a KD (SPR) of 5 nM (>50,000-fold improvement), and a Luc. EC50 of 89 nM, while an IC50 of 92 nM was reported in Karpas-422 cells. In mice, at 5.0 mg/kg (p.o.), in vivo PK analysis revealed a CMax of 1310 nM, a T1/2 of 1.6 hrs, and a % F of 36%. Limited CYP inhibition was observed (IC50 > 10 μM), with no observable affinity for hERG, and an AMES (-ve) test result for genotoxicity.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00502

 

G1

G1
G1

G1: Through a structure-based design strategy, and scaffold-hopping, the following molecule has been developed as a Soluble epoxide hydrolase (sEH) inhibitor. This enzyme has been implicated in a variety of inflammatory diseases, including arthritis, pancreatitis, and sepsis. Inhibitor design involved a highly-extensive, and rational SAR, where various functional groups were found to be critical to the observed potency, stability, and solubility. These include the bulky memantine scaffold, the 2-fluoro group, the homo-piperazine, and the aliphatic -CH2– methylene group. Against human sEH, an IC50 of 0.05 nM (50 pM) was reported, while in murine sEH, the value was found to be 0.140 nM (140 pM). In vivo pharmacokinetic analysis in rats (50 mg/kg) (p.o.) found a TMax of 0.25 hrs, a T1/2 of 5.55 hrs, a CMax of 2.92 nM, and a % F of 20.85%. Finally, efficacy was observed (in vivo) in a CFA-induced arthritis model, an L-arginine pancreatitis models, as well as an LPS-model of sepsis.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01996

 

Compound 10

Compound 10
Compound 10

Compound 10: SH2 containing tyrosine phosphatase-2 (SHP2) is a ubiquitously expressed protein, broadly implicated in RAS/MAPK, JAK/STAT, and PI3K/AKT signal transduction (which ultimately results in a strong implication in the incidence/progression of human cancers). Compound 10 was reported as an allosteric SHP2 inhibitor, designed through SBDD strategies (PDB 5EHR). In vitro, an SHP2 IC50 of 6 nM was found, with a pERK EC50 of 37 nM, and an anti-proliferative EC50 of 520 nM. In Balb-C mice (1 mg/kg)i.v., an MRT of 2.19 hrs was reported, with a T1/2 of 4.8 hrs. Finally, against hERG, an IC50 of 4.2 μM was observed.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00454

 

Compound 13A

Compound 13A
Compound 13A

Compound 13A: Using a scaffold-hopping strategy, and the derivatization of FDA approved clinical standard Cariprazine (clinical drug for schizophrenia), compound 13A was reported as a Dopamine D2/D3 receptor partial agonist/antagonist (as determined by a BRET assay). A D2R Ki value of 2.85 nM was found, while a D3R Ki value of 0.14 nM was observed (D2R/D3R = 20-fold selectivity). Against D2R GPA GαoA an EC50 of 1.70 nM was observed, while in the case of D2R mini-Gsi recruitment, an EC50 of 2.26 nM was found. In the case of D3R GPA GαoA agonism, an EC50 of 1.60 nM was reported, while for antagonism an IC50 of 4.62 nM was found. Finally, this molecule was effective in vivo in blocking cocaine self-administration in rates (1-10 mg/kg).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01624

 

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Tom Coulter, PhD

Head, Drug Discovery Programs and Partnerships

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Chief Strategy Officer

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Charlie Younger

Charlie Younger, PhD

Chief Operating Officer

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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.

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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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