Prelude Therapeutics, a clinical-stage precision oncology company, has released preclinical results indicating that its JAK2V617F mutant-selective inhibitors have disease-modifying potential for myeloproliferative neoplasms (MPNs).
MPNs are diseases of the bone marrow and blood affecting approximately 200,000 Americans. The disease can progress into acute myeloid leukemia (AML). In most cases, MPN has no cure. Current treatments inhibit both mutated and wild-type proteins with the same potency, limiting their efficacy.
The three most common MPNs are associated with mutations in certain genes, including JAK2. Prelude developed a series of mutant JAK2-selective inhibitors, the company announced last month. These compounds demonstrate a selective reduction in JAK2V617F cells compared to wild-type (WT) cells, according to Prelude. In mouse models, treatment with the inhibitors normalized white blood cells, platelets and spleen size without adverse effects, the company said.
Using quantum chemistry
On Thursday, QDX, a drug discovery company focused on quantum chemistry, revealed more information about its partnership with Prelude, first announced last year, to investigate the inhibitors further. The researchers used QDX’s quantum mechanics/molecular mechanics (QM/MM) simulation technology to study the structural differences between WT and mutant JAK2 JH2 proteins.
Quantum chemistry applies the principles of quantum mechanics to understand the behavior of atoms and molecules at the atomic and subatomic levels. In drug discovery, quantum chemistry provides more precise information about atoms and molecules than molecular mechanical methods. QM/MM models the electrons at the active site where the drug will bind, while the rest of the protein is modeled quickly using classical methods. This allows for accurate predictions of how the drug candidate will bind to the active site.
The two parts of the model, the quantum model and molecular model, are connected by a “link atom,” which prevents extra charges from forming at the border of the models. The static electrical charges in the MM region of the model are included in the QM equations through a process called electrostatic embedding, so the model shows the active site as it would appear in the human body.
Incyte’s acquisition agreement
Prelude’s JAK2V617F program will investigate the treatment potential of its inhibitors, which bind to the JAK2 H2 domain where the V617F mutation is located. Last month, Incyte agreed with Prelude to acquire the inhibitor program, including the library of preclinical inhibitor candidates, for $60 million upfront. The agreement also states that Incyte may acquire the program during the option period for $100 million. Prelude could be eligible to receive up to an additional $775 million for the advancement of candidates. Altogether, the agreement could reach up to $910 million.
Prelude’s mutant selective JAK2V617F program marks a strategic shift for the company. In early November 2025, Prelude announced that it would pause further clinical development of its SMARCA2 degrader programs, which had become its lead clinical focus in recent years, after a review of Phase 1 data in SMARCA4-mutated cancers and an internal capital allocation assessment. As of June 30, 2025, Prelude reported $77.3 million in cash, cash equivalents, restricted cash and marketable securities, with a cash runway projected into the second quarter of 2026; following the Incyte transaction and strategic update, management now expects runway into 2027, and potentially into the third quarter of 2028 if Incyte exercises its option on the JAK2 program. The company is prioritizing resources toward its preclinical JAK2V617F JH2 inhibitor and KAT6A degrader programs, while continuing discovery work on mCALR-targeted antibody drug conjugates and degrader-based antibody drug conjugates. Under the exclusive option agreement, Incyte – already a major JAK inhibitor player through Jakafi (ruxolitinib) – will provide $35 million upfront and a $25 million equity investment in exchange for an option to acquire Prelude’s JAK2V617F program for myeloproliferative neoplasms, with additional payments tied to option exercise, milestones and royalties.
Prelude will disclose more program data at the American Society of Hematology (ASH) 67th Annual Meeting taking place in Orlando, Florida, on Dec. 6-9, 2025.
