Small Molecule Candidates Targeting Primary Disease Mechanisms in DM

Published on Sat, 09/24/2016

New Review Article Series on DM

A special issue of the on-line International Journal of Molecular Sciences (edited by Prof. Lubov Timchenko) has been publishing a series of review articles on DM. To date, these articles have focused on the role of short tandem repeat expansions in RNA toxicity in DM1 and DM2 (Sznajder and Swanson, 2019) and on experiences with the development of CRISPR/Cas genome editing for DM1 (Raaijmakers et al., 2019). MDF's Research News recently highlighted one of these reviews. The latest piece in this series reviews small molecule drug development efforts aimed at DNA, RNA, and protein stages in the pathogenesis of DM1 (Reddy et al., 2019). The lead author of this review, Dr. Kaalak Reddy (University of Albany SUNY), is a former MDF Research Fellow.

Small Molecule Drugs for DM1

Small molecule compounds offer considerable advantages as putative, orally delivered drugs, a delivery route likely to be essential for systematically addressing multi-organ system diseases like DM. Knowledge of druggable chemical space (the depth and breadth of compounds with drug-like properties defined by Lipinski rule of 5 and beyond), and the analoging possible via medicinal chemistry, collectively allows: (a) high-throughput identification of parent compounds with activity at any one of multiple levels of the disease mechanisms operative in DM and (b) iterative compound optimization via analysis of Structure-Activity Relationships (SAR). Academic efforts toward discovery and development of small molecule drugs have improved in recent years, although considerable need for industry’s very large compound libraries, high-throughput capacity, and more rapid medicinal chemistry capability remains.

Dr. Reddy and colleagues frame their discussion around the molecular targets that are available to stem the pathogenesis of DM1, noting that much (but not all; e.g., AMO Pharma’s Tideglusib) progress has been made in targeting mechanisms downstream of either the expanded DNA repeats or toxic RNA. They proceed to document how that picture is changing.

The authors review, in detail, efforts for small molecule drug development for several targets/strategies, including targeting toxic RNA strategies based upon knowledge of target crystal structure (i.e., affinity for DM1 or DM2 expanded repeats), small molecule screens for toxic RNA targeting (including traditional screens, repurposed drug library screens, combinatorial chemistry screens, and specific target screens to disrupt toxic RNA-MBNL binding or nuclear foci), upregulation of MBNL protein, mis-spicing as a readout for high throughput screens, targeting CUGBP1, blocking toxic RNA transcription, targeting RAN translation, and modulating DNA expanded repeat instability. Taken together, the review serves as a digestible compendium of small molecule drug efforts in DM.

Potential for Small Molecule Drugs for DM

The authors have highlighted the breadth and depth of current efforts to bring candidate small molecule therapies into the clinic for DM. The potential for success is optimized by both the range of targets in the mainstream of established molecular mechanisms and the diversity of strategies applied to those targets. The oral bioavailability that can be achieved for small molecule drugs and their potential cost profile (versus recent pricing of biologics in other neuromuscular disease indications) also makes these efforts attractive. Finally, synergistic value may be obtained if two or more molecules receive marketing approval to address the primary pathogenic mechanisms in DM.


Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy.
Sznajder ŁJ, Swanson MS.
Int J Mol Sci. 2019 Jul 9;20(13). pii: E3365. doi: 10.3390/ijms20133365. Review.

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities.
Raaijmakers RHL, Ripken L, Ausems CRM, Wansink DG.
Int J Mol Sci. 2019 Jul 27;20(15). pii: E3689. doi: 10.3390/ijms20153689. Review.

Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules.
Reddy K, Jenquin JR, Cleary JD, Berglund JA.
Int J Mol Sci. 2019 Aug 17;20(16). pii: E4017. doi: 10.3390/ijms20164017. Review.