Staff Writer

Tensha Therapeutics, a start-up developing small-molecule bromodomain inhibitors to treat cancer by regulating the transcription of disease-associated genes, has raised $15 million in a Series A financing from HealthCare Ventures LLC, of Boston.

Tensha's lead program, presently in preclinical development, is a first-in-class small molecule aimed at the treatment of BRD4-NUT midline carcinoma – a rare, invariably fatal cancer; acute myeloid leukemias; multiple myeloma and other malignancies.

The $15 million financing represents the first investment for Tensha, which is Japanese for "to transcribe" – the idea being that the molecules function not purely by epigenetic roles, but also by inhibiting transcriptional signals.

Bromodomains, a promising new set of epigenetic drug targets, are protein modules that play critical roles in "reading" epigenetic marks on chromatin that serve as instructions for the transcription of specific genes, explained James Bradner, a hematologist-oncologist and investigator at Dana-Farber Cancer Institute in Boston and the company's scientific founder. Bradner was the first to identify and characterize potent, selective small-molecule inhibitors of BET bromodomain proteins that are important for cancer cell growth.

Cambridge, Mass.-based Tensha has an exclusive license to the technology from Dana-Farber.

"Our focus is gene regulation, because gene regulatory targets are among the most pressing targets in the cancer cell but perceptions regarding their ability to attract as drug targets have limited serious efforts in drug discovery for many compelling protein targets," Bradner explained.

About three years ago, Bradner began to study the collective families of epigenetic reader proteins, which transmit signals from gene-activating proteins to the polymerase, which expresses genes. Bradner hypothesized that inhibiting epigenetic reader proteins might block the transmission of a growth signal to the polymerase machinery.

In addition to their role as transcriptional co-activators, bromodomain proteins have been linked to mitotic memory – the "memory of being cancer after a cancer cell has divided," Bradner explained. Those clues led his team to begin an effort to inhibit bromodomain-containing proteins.

Bradner aligned with other researchers to study bromodomains more broadly and to start to build biased chemical libraries that would potentially exhibit bromodomain functions. In studies published last September in Nature, Bradner and colleagues described a small molecule, JQ1, that blocks the activity of an aberrant bromodomain-containing protein, BRD4-NUT, which causes midline carcinoma. BRD4-NUT is a fusion protein containing the BRD4 bromodomain and the nuclear protein in testis (NUT) protein that results from a chromosomal translocation. In patient-derived cell lines and mouse xenograft models, the compound blocked the protein's proliferative activity and induced tumor cells to differentiate into normal-appearing, noncancerous cells.

Subsequent studies from Bradner's laboratory, in collaboration with researchers at Cold Spring Harbor Laboratory, identified BRD4 as a therapeutic target in acute myeloid leukemia. Those studies, published online last month in Nature, extended JQ1's antiproliferative and differentiating activity in multiple model systems of leukemia. The research also suggested that inhibiting BRD4 suppresses a notorious oncogene, MYC, that is linked to a wide range of tumors.

This month, Bradner's team published findings online in Cell demonstrating that JQ1 halted the growth of multiple myeloma cells in vitro and in vivo by selective inhibition of MYC expression – again by inhibiting BRD4.

Historically, protein-protein interactions have made for difficult drug targets, Bradner admitted. However, "structural inferences suggested to me and other groups that bromodomains might be very tractable drug targets," he said. "They possess a hydrophobic pocket that satisfies the classical, predictive possibility of developing a direct-acting small-molecule inhibitor."

To further pursue bromodomains, Bradner sought partners in the pharma, nonprofit and financing worlds. HealthCare Ventures, which had partnered with Bradner in a previous oncology start-up, Shape Pharmaceuticals, was eager to sign on, said Douglas Onsi, managing director.

HealthCare Ventures will manage the company during preclinical work and partner with contract research organizations and other outside organizations needed to move the technology to the clinic, Onsi said.

This "focused company" model appeals to Bradner, as well, because it assures "a committed, focused and efficient drug discovery effort," he said.

Eli Lilly and Co., of Indianapolis, will play a role in developing the technology, Bradner added, although he and Onsi declined to provide additional details.

The financing will allow Tensha to advance its lead program through clinical proof of concept, lay the groundwork for clinical studies in other cancer indications and advance the preclinical development of bromodomain inhibitors in areas outside of oncology, according to Onsi, who declined to speculate on a timetable for any investigational new drug filings.

Although Tensha will initially focus on oncology targets, data emerging from other research labs suggested that bromodomain inhibition could play a role in many conditions, including a host of inflammatory and metabolic disorders.

"We'll start with oncology, which has the most urgent need, and more preclinical work has been done in those areas," Onsi said. "As we move forward in oncology, we'll determine whether the same compound can be applied to other indications or whether there's a need for a different profile of a compound targeted to noncancer indications."

In other financing news:

• AlphaRx Inc., of Hong Kong, raised $100,000 in a private placement. Proceeds will be used for working capital as the company expands commercialization of its Indaflex topical analgesic and develops ARX8203 for gout.

• Arrien Pharmaceuticals LLC, of Ansonia, Conn., completed a $2 million Series A financing comprised of contributions from the company founders. The start-up is using its Fragment-Field Drug Design technology to discover and develop small molecules targeting cell-signaling pathways. The company is seeking collaborations for a number of programs for which it expects to file two investigational new drug applications within the next year related to protein kinase-mediated Parkinson's, cancer and other indications. Arrien's lead candidate, ORS-1006, has shown a neuroprotective effect in cell culture models of Parkinson's and potent activity in mouse models. Its ARN-1032 and ARN-3016 have demonstrated anticancer activities in a variety of cancer cell lines.

• Cytori Therapeutics Inc., of San Diego, increased its loan with GE Capital, Healthcare Financial Services, Oxford Finance Corp. and Silicon Valley Bank to $25 million from $20 million and extended the maturity date to March 2015 from June 2013. Principal payments were deferred until September 2012. Cytori issued its lenders warrants to purchase 132,891 shares, exercisable at $3.01 per share, as part of the loan amendment. Proceeds will support Cytori's development and commercialization of adipose-derived adult regenerative cell products.