For people living with myeloproliferative neoplasms (MPNs), a group of rare blood cancers, daily life carries hidden risks. MPNs occur when the bone marrow produces too many blood cells — red cells, white cells, or platelets — disrupting normal circulation and raising the risk of serious complications.
Two common types of MPNs are polycythemia vera (PV), which causes the body to make too many red blood cells, leading to thicker blood and a higher risk of clots, and essential thrombocythemia (ET), which drives overproduction of platelets, increasing the likelihood of abnormal clotting. Both diseases are chronic and require long-term treatment.
Most patients with these diseases carry a mutation known as JAK2 (Janus kinase 2) V617F, a genetic change that keeps a critical signaling pathway permanently switched on. This mutation drives uncontrolled blood cell growth, and can lead to serious complications such as stroke, heart attack, or progression to more severe blood disorders. However, targeting this mutation has been a longstanding challenge as existing drugs can’t distinguish between mutant and healthy JAK2 proteins, leading to serious side effects.
Today, Singapore-based QDX, a computational drug discovery company, and Prelude Therapeutics, a precision oncology firm in the US, announced new details of a drug program designed to selectively target the JAK2 V617F mutation. Additionally, Prelude has entered an option deal with Incyte, the biopharma company behind Jakafi — the first JAK inhibitor approved for myelofibrosis and later for PV. The agreement gives Incyte the option to acquire the new mutant-selective JAK2 program, providing both funding and a clear path toward global development.
Under the agreement, Incyte will provide Prelude with $60 million upfront and secure the option to acquire the program for $100 million. If the program advances successfully, Prelude could earn up to $775 million in additional clinical and regulatory milestones, bringing the total potential value to $910 million, plus royalties.
Quantum insights lead to mutant-selective inhibitors
Using QDX’s advanced quantum simulations, QDX researchers mapped the subtle structural differences between the mutant and wild-type JAK2 proteins. Prelude then used this information to design drugs that specifically target the mutant protein, sparing healthy cells.
“Quantum chemistry is significantly more accurate than non-quantum methods. But traditionally it has been far too computationally expensive to use at a practical scale. QDX is no longer bound by these restrictions and this gives us two major advantages,” Loong Wang, cofounder and CEO of QDX, told DDN. “By doing quantum chemistry calculations directly at this scale, we can completely avoid many of the inaccuracies introduced by traditional force fields. For some targets, this doesn’t matter too much. But for others, this can be the difference between observing important effects that have big downstream implications, or not.”
Prelude’s structural work built on this foundation. “Our research team made significant progress discovering the first known inhibitors that bind into the JAK2 JH2 ‘deep pocket’ where the V617F mutation resides. These potent and orally bioavailable compounds demonstrate mutant specific inhibition and the potential for disease modification in multiple preclinical models of MPNs,” said Kris Vaddi, CEO of Prelude, in a previous press release.
Early preclinical studies in mice have been encouraging. The new inhibitors normalized blood cell counts, reduced spleen size, and avoided the side effects typically seen with conventional JAK inhibitors.
JAK2 is one example of where extreme-scale simulations can make undruggable targets tractable. This is the worst our technology will ever be — and we’ve made big strides since starting this program.
- Loong Wang, QDX
"These results highlight the potential of small molecules to make a meaningful difference for patients with MPNs," said Wang in the press release. "Our extreme-scale quantum chemistry and simulations enabled us to provide additional structural insights into the binding modes of Prelude’s structure-based designs of JAK2 JH2 inhibitors, and we're proud to have contributed to these efforts.”
Wang believes mutant-selective JAK2 inhibitors are just the beginning. “JAK2 is one example of where extreme-scale simulations can make undruggable targets tractable,” he told DDN. “This is the worst our technology will ever be — and we’ve made big strides since starting this program.”
The collaboration, first announced in 2024, represents a promising example of how quantum computational tools can accelerate the development of next-generation therapies. If these inhibitors continue to show promise in human trials, they may provide the first therapy that selectively shuts down the JAK2 mutation, offering hope to thousands of patients living with these rare, chronic blood cancers.
