Welcome back! In this issue of “Small Molecule Highlights” we bring you 6 new small molecules out of recent drug discovery journals. These molecules target a diverse selection of targets, including DLK, FXR, FLT3, AR, PKM2, and AcrAB-TolC. Enjoy!
IACS-52825
IACS-52825: This selective DLK inhibitor was inspired by Genentech’s GNE-8505 for the treatment of Chemotherapy-induced peripheral neuropathy (CIPN); a medical condition observed in cancer patient undergoing chemotherapy with limited treatment options. Medicinal chemists at IACS incorporated a 2,2,2-trifluoroethanol substituent off the 2-position of the imidazole core to stabilize a frustrated water interaction within the binding pocket, and to create ancillary binding interactions with the protein backbone of the P-loop (Val131 and Ser 133) via the trifluoromethyl group. The combined multipolar and water bridging interactions, as well as the judicious incorporation of fluorine at the tail end of the bicylopentane substituent to mitigate Cyp metabolism, helped propel this candidate into IND enabling studies. IACS-52825 exhibited a dose-dependent response in a mouse model of CIPN, with symptoms largely reversing in one study after a 30 mg/kg treatment regiment (p.o., daily, 27 days). Unfortunately, further evaluation in higher primates revealed optic nerve swelling as a primary, albeit reversible, toxicity associated with chronic dosing. As no therapeutic window could be identified, IACS-52825 was dropped as a candidate for progression into clinical trials.
Reference: https://pubs.acs.org/10.1021/acs.jmedchem.3c00788
HPG1860
HPG1860: Medicinal chemists at Hepagene Therapeutics used a scaffold hopping approach to quickly identify a tractable scaffold for further lead optimization. Using GW4064 as inspiration, chemists at Hepagene incorporated a benzothiazole to reduce the entropy of binding to the target and further optimized the relative position of the methoxy and carboxylic acid groups to enhance interaction with R331 of the binding pocket. A small contribution to binding was also made by the pendant methyl group of the piperazine linker, which filled a previously unutilized hydrophobic recess delineated by A291 and M328 of the protein. Addition of the cyclopropyl group, used to replace an isopropyl in previous iterations, increased activity in both the cellular and biochemical assays. HPG1860 exhibited nanomolar activity in a TR-FRET based FXR bioactivity assay (EC50 = 5 nM) and a cellular FXR-luciferase reporter assay (EC50 = 18 nM). Pharmacokinetic characterization of the lead compound revealed good oral bioavailability across species; 52, 55 and 79% across mouse, rat and dog, respectively. A demonstrable PD effect was observed in a mouse model of CCl4 induced NASH, with HPG1860 significantly decreasing markers of liver injury and inflammation compared to OCA (commonly used FXR tool compound). Currently, HPG1860 has progressed into clinical trials, with phase IIa results to be communicated soon.
Reference: https://doi.org/10.1021/acs.jmedchem.3c00456
BDM91514
BDM91514: A joint venture between the Drug and Molecules for Living Systems and the Center for Infection and Immunity at the University of Lille, France, was responsible for developing this piperazine based small molecule inhibitor targeting AcrAB-TolC efflux pumps (implicated in bacteria multi-drug resistance). The medicinal chemistry team identified three derivatization points (piperazine, 3-chloro of the pyridine and the 5-position of the pyridine). Unfortunately, modifications to the piperazine and the 3-chloro group of the pyridine were not tolerated as these groups make key binding interactions with Asp408 and Lys904 (via a halogen bonding interaction), respectively. Operating under a very constrained SAR, the team looked for alternate contact points within the binding site and leveraged residues Glu947 and Asp951 for this purpose. Towards this end, a 5-oxadiazole substituent with an ethylamine arm was incorporated to interact with Glu947/Asp951. The team’s hypothesis was supported in engineered E. coli containing mutations to the Glu and Asp residues of Acbr. BDM91514 was shown to enhance the efficacy of a panel of 8 commonly used antibiotics (2-8 fold), and was found to be stable in mouse plasma (t1/2 > 6h) and mouse liver microsomes (t1/2 > 40 min).
Reference: https://doi.org/10.1016/j.ejmech.2023.115630
Compound 34f
Compound 34f: This entirely Czech led initiative to develop a new generation of selective FLT3 inhibitors for the treatment of AML provided an excellent case study in scaffold hopping. A variety of purine like isosteric scaffolds were sampled, and once the ideal scaffold selected, further SAR was conducted at the positions currently occupied by the phenyl and trans-cyclohexyldiamine to dial down activity against CDK2. Compound 34f exhibited exquisite potency against FLT3 harboring the ITD and D835Y activating mutations (4 nM and 1 nM, respectively), while maintaining selectivity (>100 fold over CDK2). FLT3 selectivity was further supported in cell viability studies conducted in FLT3 dependant (MV4-11 and MOLM-13) and independent (NOMO-1 and ML-2) cell lines. Flow cytometry analysis of compound treated MV4-11 cells confirmed inhibition of signalling pathways downstream of FLT3, and elucidated markers of growth arrest (at G1) in treated cells. Tumor regression (>60%) without body weight loss was observed in immunodeficient mice bearing subcutaneous MV4-11 xenografts treated with compound 34f (5 and 10 mg/kg i.p.). The authors hinted at further optimization of the scaffold.
Reference: https://doi.org/10.1021/acs.jmedchem.3c00575
BWA-522
BWA-522: Yet another entrant into the PROTAC therapeutic space targeting the androgen receptor (AR), this compound is the first to target the receptor’s N-terminal Domain (NTD). The protein binding portion of the compound was inspired by a bisphenol-A derivative isolated from marine sponge. Optimization of linker length and composition (rigid vs. flexible), as well as linker attachment to the CRBN ligand (meta vs. ortho) furnished BWA-522. The PROTAC exhibited sub-micromolar degradation in VCAP cells containing either full length AR (DC50 = 0.73 μM) or mutant AR-V7 (DC50 = 0.63 μM). Mechanism of action was confirmed by co-treatment with MG132 (proteosome inhibitor), MLN4924 (E1 enzyme inhibitor), and excess CRBN ligand. In vivo pharmacokinetic analyses in mice (2 mg/kg i.v. and 5 mg/kg p.o.) revealed a half-life of 8.2/7.9 hrs (i.v./p.o.), a maximal half-life of 0.1/4.7 hrs (i.v./p.o.) and an oral bioavailability of 40% (69% in beagle). In vivo efficacy was demonstrated in a murine LNCaP xenograft model where BWA-522 effectively inhibited tumor growth over the course of 28 days (60 mg/kg, p.o., daily).
Reference: https://doi.org/10.1021/acs.jmedchem.3c00585
CIAC001
CIAC001: Medicinal chemists at the Changchun Institute of Applied Chemistry (China) prepared this derivative of cannabidiol (CBD) for the treatment of morphine induced addiction. The goal was to retain the anti-inflammatory properties of CBD while decreasing its neurotoxicity. CIAC001 effectively reduced inflammation in LPS-stimulated BV-2 microglial cells, with a therapeutic index 30 fold higher than that of CBD. In mouse models of opioid withdrawal, behavioral sensitization, and conditioned place preference, CIAC001 was able to inhibit opioid induced/conditioned behavior with doses as low as 0.2 mg/kg (i.p.). Pharmacokinetic analyses in mice revealed improved blood brain barrier penetration compared to CBD (2-fold increase in Cmax) and a brain/plasma ratio exceeding 200% within the first 3 hours of oral administration (10 mg/kg). A photoaffinity probe was appended to CIAC001 to identify its target via pull down. PKM2 was identified and binding substantiated by CETSA (ΔTm = 3.9 ± 1.3 °C). The authors propose that the molecule stabilizes PKM2 tetramers within the cytosol, preventing monomer translocation to the nucleus and mitigating neuronal inflammation.
Reference: https://doi.org/10.1021/acs.jmedchem.3c01029