Global Blood Therapeutics Inc. (GBT) came charging out of the gate Thursday with a $40.7 million Series A, becoming the first company "organically constructed, formed and launched" from the West Coast office of Third Rock Ventures LLC, according to Mark A. Goldsmith, the company's CEO and a Third Rock venture partner.

GBT's "SHAPE" platform is designed to enable the discovery and development of oral, small-molecule drugs to revolutionize the treatment of chronic genetic blood disorders by changing the shapes of key blood proteins to modify their functions. The company expects compounds generated from the platform to lead to therapeutic breakthroughs in illnesses such as sickle cell disease (SCD) – the company's first target.

SCD – one of the earliest rare genetic diseases to be defined on a molecular basis – is caused by a single mutation that alters the oxygen-transport protein hemoglobin. Like many genetic blood disorders, a single amino acid change in the sequence of the key protein causes the characteristic "sickling" of red blood cells, resulting in the aggregation and clogging of small blood vessels.

Despite progress in diagnosing and understanding the genetic underpinnings of the disease, which affects 100,000 patients in the U.S. and more than 15 million worldwide, treatment options focus mainly on supportive care – usually in a hospital setting – with no therapies addressing the underlying cause. Many patients suffer a lifetime of episodic pain, vasoocclusion, anemia and organ damage and face a high risk of stroke and renal insufficiency.

"It all comes back to this one amino acid," Goldsmith told BioWorld Today. "Recognizing that hemoglobin can assume multiple conformations, our approach is to use the binding energy of a small molecule attached to or associated with hemoglobin in a very specific way to coax the molecule back into a shape that is favorable for oxygen binding.

"We have good reason to believe that, if we can achieve that on a molecular basis, we can markedly overcome the fundamental adverse physiology associated with this mutation," he added.

Long term, GBT expects to build a pipeline of therapies for chronic blood-based diseases and genetic disorders using allosteric modulation to change the shapes of key blood proteins. To that end, the SHAPE platform seeks to marry advanced computational biology and protein-ligand modeling with medicinal chemistry and empiric screening capabilities. GBT hopes the approach will result in the development of potent, orally available compounds with rapid onset of action and low toxicity.

"Blood is one of the largest and most accessible organs and is a rich source of biologically and clinically validated targets," Goldsmith said. "We know how to deliver drugs into the blood space, and we can easily obtain samples on a regular basis to monitor the disease process."

The company's foundation was laid several years ago in the offices of Third Rock's Charles Homcy and Craig Muir, who recognized that chronic blood disorders often resulted from well-validated genetic disorders with large unmet medical needs. Understanding precisely what target to address represented "a very exciting opportunity," Goldsmith said. "We spent a great deal of time thinking creatively about how we could introduce a different type of drug into this therapeutic area."

About a year ago, Third Rock seeded the company, which began working quietly to refine the technology.

GBT has an impressive pedigree in blood biology as well as drug discovery and development. In addition to Homcy and Muir, founders include David Phillips, co-founder of COR Therapeutics, which was acquired in 2001 by Millennium Pharmaceuticals Inc. (now part of Takeda Pharmaceutical Co. Ltd.), and co-founder with Homcy of Portola Pharmaceuticals Inc., of South San Francisco; and University of California, San Francisco, researchers Matthew Jacobson, professor of pharmaceutical chemistry; Andrej Sali, professor of bioengineering and therapeutic sciences; and Jack Taunton, associate professor of cellular and molecular pharmacology.

In addition to Goldsmith, former CEO and current executive chairman of Constellation Pharmaceuticals Inc., the management team includes acting chief scientific officer Brian Metcalf, who served as executive vice president and chief drug discovery scientist at Incyte Corp. and senior vice president, discovery chemistry and platform technologies, at SmithKline Beecham (now GlaxoSmithKline plc), and chief technology officer Craig Muir, a Third Rock partner, former senior vice president at Codon Devices and former vice president, platform technologies at Millennium.

Goldsmith declined to disclose a development timetable for the lead compound but said the company already is building a portfolio of additional targets behind SCD that have "genetic validation, well-understood mechanisms and well-defined targets." While focusing on SCD, GBT plans to advance "multiple targets against multiple diseases," he said, with the Series A structured around those financial projections.

With eight employees, GBT expects modest growth as it prepares to move into offices in South San Francisco this fall. Although the company likely will need additional capital down the road, Goldsmith said, future funding could come in the form of partnerships rather than venture financings.

"We've already had interest from other potential investors," he said, "and we're confident these programs also will generate interest from potential business partners over time."