CDK7 inhibitor THZ1 offers hope for patients with SCLC

Syros Pharmaceuticals recently published two studies that further demonstrate the potential of covalent CDK7 inhibitor THZ1, the company’s lead preclinical program, in neuroblastoma[1] and small cell lung cancer (SCLC)[2]. Tumor shrinkage was achieved without evidence of systemic toxicity. In June 2014, Syros reported the discovery of THZ1 in Nature[3].

Syros is a Watertown, MA-based biotech startup founded by scientists from MIT and Harvard. Nancy Simonian, the well-known former chief medical officer of Millennium Pharmaceuticals, is the chief executive officer of Syros. Nobel laureate Phillip Sharp who cofounded Biogen Idec has taken a seat on the Syros board of directors.

In April 2013, this nine-employee company raised $30 million in a Series A financing from ARCH Venture Partners, Flagship Ventures, and WuXi PharmaTech. In October 2014, Syros raised $53 million in a Series B financing from 16 investors including Polaris Partners, Aisling Capital and Redmile Group.

THZ1 is the first covalent CDK7 inhibitor that has been demonstrated to target a remote cysteine residue (Cys312) located outside of the kinase domain, providing an unanticipated means of achieving covalent selectivity. CDK7 phosphorylates the C-terminal domain of RNAP polymerase II, facilitating efficient transcriptional initiation, pause release and elongation.

SCLC accounts for 10-15% of lung cancer cases. It is the most aggressive form of lung cancer with an overall 5-year survival less than 5%, spreading much more quickly than non-small cell lung cancer. The combination of cisplatin or carboplatin with etoposide (EP) remains the standard treatment for SCLC.

No new drugs for SCLC have been approved for many years. Although small cell lung tumors have many mutated genes, none of these is known to be a driver, in other words, none makes a good target.

Cancer Research UK/AstraZeneca intend to test MCT1 inhibitor AZD3965 targeting cancer metabolism in patients with SCLC[4]. Other new drugs (for clinical data see ASCO2014) for SCLC include vandetanib (failed), veliparib (plus EP), BMN673 (second line), rilotumumab (failed), OMP-59R5 (plus EP), and LDE225 (plus EP).

[1] Cell. 2014, 159(5), 1126-1139.

[2] Cancer Cell. 2014, 26(6), 909-922.

[3] Nature. 2014, 511(7511), 616-620.

[4] Clin Cancer Res. 2014, 20(4), 926-937.

Patent: WO2014063068.

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