The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors are currently under clinical investigation, whereas there are no reports to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to identify X-ray cocrystal structures of five diverse fragment hits bound to SOS2.

SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. In this report, we detail the design and discovery of MRTX0902-a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRASG12C PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.

KRAS mutations are the most common activating mutations in human cancer that ultimately lead to hyperactivation of the MAPK pathway and uncontrolled growth. KRAS functions as a small GTPase that cycles through its GTP-loaded “on” state and its GDP-loaded “off” state, a highly regulated process that is crucial for normal cell proliferation and survival. The guanine nucleotide exchange factor (GEF) SOS1 plays a critical role in this process by regulating the “on/off” state of KRAS. The protein-protein interaction between SOS1 and KRAS facilitates turnover of KRAS from the GDP-loaded inactive state to its activated and GTP-loaded state, a critical step to enable productive KRAS effector binding and activation of downstream signaling. The KRASG12C inhibitor, adagrasib (MRTX849), irreversibly binds to the GDP-loaded inactive conformation of KRASG12C and has recently shown encouraging clinical activity across several cancer types. As adagrasib binds preferentially to the inactive state of KRAS, blockade of SOS1 is anticipated to shift KRASG12C into the adagrasib-susceptible GDP-loaded state. Furthermore, this combination strategy could be used to target other mutant-driven cancers within the MAPK pathway using the appropriate KRASmut inhibitors and/or inhibitors of other targets within the MAPK pathway including MEK or EGFR. MRTX0902 was identified using iterative structure-based design as a selective inhibitor of SOS1 that demonstrates an IC50 value of 2 nM in a SOS1 HTRF binding assay and 30 nM in an MKN1 cellular assay. In pharmacokinetic evaluation across species, MRTX0902 demonstrated low extraction ratios and moderate to high bioavailability in mice, rats, and dogs. In preclinical models, MRTX0902 augmented the antitumor activity of adagrasib and other selected therapies. The design, discovery, and preclinical characterization of the potential best-in-class candidate MRTX0902 will be described. Citation Format: John M. Ketcham, David M. Briere, Aaron C. Burns, James G. Christensen, Robin J. Gunn, Jacob Haling, Anthony Ivetac, Shilpi Khare, Jon Kuehler, Svitlana Kulyk, Jade Laguer, John D. Lawson, Krystal Moya, Natalie Nguyen, Peter Olson, Lisa Rahbaek, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Darin Vanderpool, Xiaolun Wang, Matthew A. Marx. Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB505.

Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP -deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.

La presente invention concerne des composes de formule (I) qui sont utiles comme inhibiteurs de PHD, leurs compositions pharmaceutiques, des procedes de traitement d'etats associes avec HIF, des procedes de fabrication de leurs composes et intermediaires.

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the β-position of the azaindole core thereby altering physical properties by lowering calculated logD values (cLogD) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.