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Small Molecule Highlights #04 – December 2022

The nine small molecules highlighted below feature an expansive set of target-oriented binding strategies, including dual inhibition, agonism, antagonism, targeted-protein degradation, along with the more canonical, orthosteric inhibition profile. Design efforts were largely centered around structure-based drug design (SBDD), and scaffold-hopping, focused on a diverse list of protein targets, including 1) Kinases: PI3K, LRRK2, DLK, ZLK, 2) GPCRs: GPR55, 3) Proteases: CatL/CatS, as well as 4) Chemokine receptors: CCR5.

Small Molecule Highlights #04 – December 2022



GDC-0077: This small molecule with a benzoxazepine core is an ATP-competitive phosphatidylinositol 3-kinase (PI3K) inhibitor, as well as a degrader of p110α (which is a catalytic sub-unit of PI3K). Strong selectivity (>300-fold) for PI3Kα was observed (PI3K Ki α/β/γ/δ = 0.034/99.7/18.2/12.2 nM), as well as lipophilic ligand efficiency (LLE) of 7.4. A co-crystal with p110α (PDB 8EXV) indicated H-bonds between the -CHF2– and Ser774. In HCC1954 pPRAS40, an EC50 of 19 nM was observed, along with an oral bioavailability of 58% (at 50 mg/kg, mouse). In vivo activity was found in an HCC1954 PI3KCA­-mutant breast cancer (BC) xenograft model, with a TGI of 149%.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01422



P7: Bi-functional molecule was identified as a degrader of Son of sevenless homolog 1 (SOS1), a protein involved in RAS/MAPK signalling, which is implicated in KRAS mutant colorectal cancer (CRC). Molecular design followed a structure-based design strategy via a cereblon-SOS1 co-crystal, and the use of a lenalidomide E3 ligase. Percent degradation of SOS1 (at 1 μM, 6 hrs) in SW620 CRC cells was found to be 64% (rising up to 92% after 48 hrs). In patient-derived organoids (PDO), SOS1 degradation was maintained (1 μM, 24 hrs), representing an improvement relative to clinical standard BI3406. Finally, cytotoxicity was not observed in non-cancerous HPNE cells (up to 100 μM).

Reference: https://doi.org/10.1021/acs.jmedchem.2c01300



DN-1289: Dual inhibitor of both dual leucine zipper kinase (DLK), and leucine zipper-bearing kinase (LZK), which are implicated in neuronal degeneration, and amyotrophic lateral sclerosis (ALS). Biochemical assays against DLK/LZK found IC50 values of 17/40 nM, while EC50 values against DLK p-c-Jun/LZK p-c-Jun were 88/711 nM. A co-crystal of a structural analog (PDB 8DEG) found interactions with both hinge/P-loop residues. In vivo pharmacokinetic analyses revealed a T1/2­ of 4.6 hrs, with an oral bioavailability of 52% (3 mg/kg, rat). PK was also determined in both mouse and cyno models. Efficacy was also observed in an acute ONC model, as well as a SOD-1 model of ALS.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01056

Compound 25

Compound 25 LRRK2
Compound 25

Compound 25: This 1-heteroaryl-1H-indazole with a unique spiro[2.2]pentane motif, is an ATP-competitive inhibitor of leucine-rich repeat kinase 2 (LRRK2), with implications in Parkinson’s Disease (PD). A co-crystal of the LRRK2-CHK1 chimera (PDB 8E81) indicated prospective hydrophobic interactions with the spiro-nitrile functional group. In a kinase inhibition assay, an LRRK2 IC50 of 0.9 nM was found, with a Cellu IC50 of 0.3 nM. Also, a decrease of LRRK2 pS935 was found, with an EC50 of 0.18 nM. A negative AMES test was found in 5 strains, with a low projected human dose of 45 mgs.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01605

Compound 24

Compound 24
Compound 24

Compound 24: As a thienopyrimidine, this molecule was identified as an inhibitor of G-protein coupler receptor 55 (GPR55), which is an orphan GPCR. Structurally, this analog originates from GPR55 antagonist ML192 (discovered via high-throughput screening). In a β-arrestin recruitment assay (in CHO cells) found an IC50 of 0.28 μM. Molecular docking analyses suggest useful hydrophobic interactions with the di-methyl motif. Limited affinity was found against both cannabinoid receptors, CB1/CB2 (at 4 μM) in a competitive binding assay. In a SRE assay, this compound was found to be a weak inverse agonist of GPR55, and in the presence of LPI, it was found to be a GPR55 antagonist.

Reference: https://doi.org/10.1021/acsmedchemlett.2c00325

Compound 72

Compound 72
Compound 9Q

Compound 72: This small molecule was found to be an agonist of stimulator of interferon genes (STING), with implications in oncology. In THP1-dual STING, an EC50 of 1.58 μM, while against THP1-dual STING-KO the EC50 value was found to be >100 μM. MTS, in both THP1-dual STING, as well as STING-KO, the EC50 was also seen to be > 100 μM. In rat blood plasma stability study,78.7% was found (after 1 hr incubation), which 60.5% at 2 hr. STING-TBK1-IRF3 signalling was also studied, along with pSTING (Ser366), which suggested an increase if IFNβ. High selectivity was found for human STING compared to mouse STING.

Reference: https://doi.org/10.1016/j.ejmech.2022.114943



B1a: Dual inhibitor of cathepsin L (CatL), and cathepsin S (CatS) was developed as an anti-cancer strategy with anti-metastatic effects in BxPC-3, and PANC-1 cells. Inhibitor design involved a scaffold-hopping  strategy (using 24 analogs), with comparative analysis against standard ASPER-29. Selectivity was observed against CatL/CatS relative to CatK (CatL/CatS/CatK IC50 = 4.10/1.79/100 μM). Evidence for anti-metastasis was found in both a wound-healing, and transwell chamber assay.

Reference: https://doi.org/10.1016/j.bmcl.2022.129087

Compound 25

Compound 25 CCR5
Compound 25

Compound 25: This small molecule, with a unique tropane linker was identified as a C-C chemokine receptor 5 (CCR5) antagonist. CCR5 antagonism has been established as a useful anti-HIV-1 strategy (as seen by the FDA approved clinical standard Maraviroc). In a HEK293 assay studying CCR5 binding activity, an IC50 of 8.34 nM (equipotent with Maraviroc). Studies against various relevant strains of HIV-1 found broad activity HIV-1 Ba-L/YU-2/SF162/KIZ001/KIZ006 EC50 = 16.9/8.7/15.9/7.8/12.6 nM. In a CCR5-Tropic integrase resistant strain HIV-1 YU-2 (G140S/Q148H), an EC50 of 4.34 nM was found. Pharmacokinetics in SD rats (10 mg/kg, orally) found a T1/2 of 10.3 hrs, a Tmax of 2.0 hrs, a MRT of 13.2 hrs, and a bioavailability (F) of 15.7 %.

Reference: https://doi.org/10.1021/acs.jmedchem.2c01383

Compound 7e

Compound 7e
Compound 7e

Compound 7e: This 1,2,3-triazole benzenesulfonamide was found as a human α-carbonic anhydrase (hCAinhibitor. Structural design involved a tail-method, with hybridization with 1,3-dioxoisoindoline-5-carboxylate. Extensive studies against various CA isoforms found broad activity hCA I/II/IV/IX/XII Ki  IC50 = 48.1/9.72/18.28/22.85/19.72 nM, which represented an improvement relative to the clinical standard AAZ. Molecular modelling/docking studies with hCA II (PDB 3HS4) found several interactions, including H-bonds, and pi-pi- stacking events with various residues (including Thr, Gly, Phe, and Zn2+).

Reference: https://doi.org/10.1016/j.bmc.2022.117111

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Diana Kraskouskaya

Diana Kraskouskaya, PhD

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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. ​

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