Drug discovery

Repligen and quinazoline for a SMA treatment

Families of Spinal Muscular Atrophy (FSMA) announced that it has entered into a groundbreaking exclusive license agreement with Repligen Corporation for the development of a potential treatment of Spinal Muscular Atrophy (SMA).
FSMA made investments of $13 million during the last decade to bring this specific program to the cusp of clinical development. Through FSMA’s leadership, the research has resulted in a drug candidate, Quinazoline495, that treats the underlying cause of SMA. In fact the licensed compounds increase the production of SMN in cells derived from patients. In preclinical studies, the drug has been shown to efficiently cross the blood brain barrier - a critical feature for a neurological drug - and prolong survival significantly in two different transgenic mouse models of SMA.

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A drug candidate for SMA: PTK-SMA1

Paratek Pharmaceuticals and Families of Spinal Muscular Atrophy announced that a jointly funded drug development program for Spinal Muscular Atrophy has been awarded a multi-million dollar cooperative agreement from NINDS.
The five-year cooperative agreement encompasses pre-clinical drug development up to the time of an Investigational New Drug Application (IND) to the FDA. The program is focused on developing a novel small molecule of the tetracycline family, PTK-SMA1, from within Paratek's propriety compound library. The potential for success of the drug candidate is evaluated at key stages of the development using quantitative go/no-go milestones that have been established in the agreement between Paratek and the NINDS. The Krainer Laboratory at Cold Spring Harbor Laboratory and the Hastings Laboratory at Rosalind Franklin University are also key collaborators in the program and will also receive funding under the NINDS cooperative agreement.

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Towards the drug: FSMA program

FSMA program for drug discovery

The ultimate goal at FSMA is to find an effective treatment and cure for SMA. In order to achieve this FSMA has invested substantial funds in pre-clinical SMA drug development since 2000.
Traditionally it has been difficult to attract major pharmaceutical companies to conduct research for orphan diseases like SMA, which have small patient populations with small potential for profit. Therefore FSMA has taken the strategy of providing seed funding to encourage biotech and pharmaceutical partners to engage in SMA drug research. The objective is to reduce the risk for industrial partners by simultaneously providing funding, research tools, scientific expertise, and established clinical networks. This strategy effectively lowers the barriers for embarking in SMA drug discovery.

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Towards the drug: tetracycline

Tetracycline derivatives to correct SMN2 splicing

Paratek Pharmaceuticals' interest in developing a small molecule drug discovery program in the Spinal Muscular Atrophy (SMA) therapeutic area started back in 2002 when a portion of Paratek’s library of over 2,000 modified tetracycline (TC) derivatives were screened in a SMA relevant in-vitro assay.

The initial concept of screening TC derivatives for SMA came from their structural similarity with aclarubicin A. This chemotherapeutic drug was reported in 2001 to be active in cellular assays relevant to SMA: it enhanced the inclusion of exon 7 in the splicing of SMN2 pre-messenger RNA (pre-mRNA) and restored normal SMN protein levels in an SMA patient-derived cell line.

However, aclarubicin is toxic and not suitable for clinical development. Paratek surmised that nontoxic TC derivatives could potentially increase full-length mRNA production and SMN protein synthesis from the SMN2 gene. The discovery of a nontoxic TC derivative would be an important finding leading to a potential treatment for SMA.

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