Tetracycline Derivatives

Tetracycline Derivatives as SMN2 Splicing Modifiers for the Treatment of SMA

Dr Higgins
Paratek Pharmaceuticals, USA

Saturday 15th January 2011

Paratek Pharmaceuticals is at a compound optimization stage in the drug discovery process. The company is targeting spinal muscular atrophy (SMA). Paratek’s strategy involves the identification and development of compounds that mediate the increased inclusion of SMN2 exon 7. Paratek has conducted a Structure-Activity Relationship (SAR) program that began with the identification of a lead compound through the screen of a tetracycline library. They have identified a group of potential candidates. One of these will be selected as a final candidate for intrathecal administration in children with SMA.

Paratek has a strong assay suite that includes cell and mouse models. They have identified compounds that increase the expression of full-length SMN2 mRNA and protein. They have supportive data in the mouse brain, using intracerebroventricuar administration. TACT advised the company to carefully evaluate the feasibility and implications of this route of administration for a chronic disease, although we recognize that, under some circumstances, intrathecal administration to children may be possible. Safety may be significantly defined by dose and the required frequency of administration in the case of direct administration to the CNS. We suggest contacting neurosurgical and safety experts, as well as regulatory experts, SMA clinicians and patient groups to better define the path to the clinic including choice of patient population which will be very important.

12 Apr 2017